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Threshold of Toxicological Concern - an update for non-genotoxic carcinogens

Batke, M, Afrapoli, FM, Kellner, R, Rathman, J, Yang, C, Cronin, MTD and Escher, S (2021) Threshold of Toxicological Concern - an update for non-genotoxic carcinogens. Frontiers in Toxicology. ISSN 2673-3080

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Open Access URL: https://doi.org/10.3389/ftox.2021.688321 (Published version)

Abstract

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with 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 tumour incidence were compared with no observed effect levels (NOEL) 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 CPDB as either non- or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a data set 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 including RepDose, ToxRef and COSMOS DB. Further, an effective tumour dose (ETD10) was calculated and compared to 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 region of the 5th percentiles of the distributions.

Excluding these 25 compounds resulted in significantly higher, but comparable 5th percentile chronic NOEL and BMDL10 values, while the 5th 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, including non_genotoxic carcinogens.

Item Type: Article
Subjects: R Medicine > RA Public aspects of medicine > RA1190 Toxicology. Poisions
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Frontiers Media
Date Deposited: 24 Jun 2021 07:18
Last Modified: 24 Jun 2021 08:00
DOI or Identification number: 10.3389/ftox.2021.688321
URI: https://researchonline.ljmu.ac.uk/id/eprint/15093

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