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Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as...

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Autores principales: Batke, Monika, Afrapoli, Fatemeh Moradi, Kellner, Rupert, Rathman, James F., Yang, Chihae, Cronin, Mark T. D., Escher, Sylvia E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915827/
https://www.ncbi.nlm.nih.gov/pubmed/35295144
http://dx.doi.org/10.3389/ftox.2021.688321
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author Batke, Monika
Afrapoli, Fatemeh Moradi
Kellner, Rupert
Rathman, James F.
Yang, Chihae
Cronin, Mark T. D.
Escher, Sylvia E.
author_facet Batke, Monika
Afrapoli, Fatemeh Moradi
Kellner, Rupert
Rathman, James F.
Yang, Chihae
Cronin, Mark T. D.
Escher, Sylvia E.
author_sort Batke, Monika
collection PubMed
description The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class, even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumor incidence were compared with no observed effect levels (NOELs) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the Carcinogenicity Potency DataBase (CPDB) as either non-genotoxic or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a dataset of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well-known repositories, such as RepDose, ToxRef, and COSMOS DB. Further, an effective tumor dose (ETD10) was calculated and compared with the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in the region of the fifth percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher but comparable fifth percentile chronic NOEL and BMDL10 values, while the fifth percentile EDT10 value was slightly higher but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non-genotoxic compounds, such as non-genotoxic carcinogens.
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spelling pubmed-89158272022-03-15 Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens Batke, Monika Afrapoli, Fatemeh Moradi Kellner, Rupert Rathman, James F. Yang, Chihae Cronin, Mark T. D. Escher, Sylvia E. Front Toxicol Toxicology The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class, even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumor incidence were compared with no observed effect levels (NOELs) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the Carcinogenicity Potency DataBase (CPDB) as either non-genotoxic or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a dataset of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well-known repositories, such as RepDose, ToxRef, and COSMOS DB. Further, an effective tumor dose (ETD10) was calculated and compared with the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in the region of the fifth percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher but comparable fifth percentile chronic NOEL and BMDL10 values, while the fifth percentile EDT10 value was slightly higher but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non-genotoxic compounds, such as non-genotoxic carcinogens. Frontiers Media S.A. 2021-06-24 /pmc/articles/PMC8915827/ /pubmed/35295144 http://dx.doi.org/10.3389/ftox.2021.688321 Text en Copyright © 2021 Batke, Afrapoli, Kellner, Rathman, Yang, Cronin and Escher. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
Batke, Monika
Afrapoli, Fatemeh Moradi
Kellner, Rupert
Rathman, James F.
Yang, Chihae
Cronin, Mark T. D.
Escher, Sylvia E.
Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title_full Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title_fullStr Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title_full_unstemmed Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title_short Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens
title_sort threshold of toxicological concern—an update for non-genotoxic carcinogens
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915827/
https://www.ncbi.nlm.nih.gov/pubmed/35295144
http://dx.doi.org/10.3389/ftox.2021.688321
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