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Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds

Robert Thomas Orcid Logo, David J. Ponting Orcid Logo, Andrew Thresher Orcid Logo, Joerg Schlingemann Orcid Logo, John W. Wills Orcid Logo, George Johnson Orcid Logo

Archives of Toxicology, Volume: 99, Issue: 3, Pages: 983 - 993

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1007/s00204-024-03951-8

Abstract

The tumorigenic dose 50 (TD50) is a widely used measure of carcinogenic potency which has historically been used to determine acceptable intake limits for carcinogenic compounds. Although broadly used, the TD50 model was not designed to account for important biological factors such as DNA repair and...

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Published in: Archives of Toxicology
ISSN: 0340-5761 1432-0738
Published: Springer Science and Business Media LLC 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa68652
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spelling 2025-02-25T12:07:09.2857778 v2 68652 2025-01-05 Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2025-01-05 MEDS The tumorigenic dose 50 (TD50) is a widely used measure of carcinogenic potency which has historically been used to determine acceptable intake limits for carcinogenic compounds. Although broadly used, the TD50 model was not designed to account for important biological factors such as DNA repair and cell compensatory mechanisms, changes in absorption, etc., leading to the development of benchmark dose (BMD) approaches, which use more flexible dose–response models that are better able to account for these processes. Using a nitrosamine dataset as a case study, we compare the impact of moving to a BMD-based limit as opposed to a TD50-based limit. Although there are differences in individual potency estimates between the two approaches for some compounds, we show that the key metrics such as the 5th percentile of the respective potency distributions, used when calculating class-specific default acceptable intakes, are not greatly affected. Furthermore, potency estimates for nitrosamine compounds relevant to read-across do not vary by more than a factor of 3, which is little in the context of the inherent variability in a biological response, in an overall landscape wherein potencies can vary by four orders of magnitude. This suggests a move to BMD-based limits is achievable without significant disruption to existing limits while utilising a more robust methodology. Journal Article Archives of Toxicology 99 3 983 993 Springer Science and Business Media LLC 0340-5761 1432-0738 Nitrosamines; Acceptable intake; TD50; Benchmark dose (BMD); Dose–response modeling; Drug impurities 1 3 2025 2025-03-01 10.1007/s00204-024-03951-8 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 2025-02-25T12:07:09.2857778 2025-01-05T10:38:56.6425689 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Robert Thomas 0000-0003-0261-8720 1 David J. Ponting 0000-0001-6840-2629 2 Andrew Thresher 0000-0001-9470-1606 3 Joerg Schlingemann 0000-0003-4799-1086 4 John W. Wills 0000-0002-4347-5394 5 George Johnson 0000-0001-5643-9942 6 68652__33526__e7b56db873124656ad3e3b9130939956.pdf 68652.VoR.pdf 2025-02-06T15:27:54.4828211 Output 2051491 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
spellingShingle Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
George Johnson
title_short Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
title_full Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
title_fullStr Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
title_full_unstemmed Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
title_sort Critical comparison of BMD and TD<sub>50</sub> methods for the calculation of acceptable intakes for N-nitroso compounds
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 Robert Thomas
David J. Ponting
Andrew Thresher
Joerg Schlingemann
John W. Wills
George Johnson
format Journal article
container_title Archives of Toxicology
container_volume 99
container_issue 3
container_start_page 983
publishDate 2025
institution Swansea University
issn 0340-5761
1432-0738
doi_str_mv 10.1007/s00204-024-03951-8
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description The tumorigenic dose 50 (TD50) is a widely used measure of carcinogenic potency which has historically been used to determine acceptable intake limits for carcinogenic compounds. Although broadly used, the TD50 model was not designed to account for important biological factors such as DNA repair and cell compensatory mechanisms, changes in absorption, etc., leading to the development of benchmark dose (BMD) approaches, which use more flexible dose–response models that are better able to account for these processes. Using a nitrosamine dataset as a case study, we compare the impact of moving to a BMD-based limit as opposed to a TD50-based limit. Although there are differences in individual potency estimates between the two approaches for some compounds, we show that the key metrics such as the 5th percentile of the respective potency distributions, used when calculating class-specific default acceptable intakes, are not greatly affected. Furthermore, potency estimates for nitrosamine compounds relevant to read-across do not vary by more than a factor of 3, which is little in the context of the inherent variability in a biological response, in an overall landscape wherein potencies can vary by four orders of magnitude. This suggests a move to BMD-based limits is achievable without significant disruption to existing limits while utilising a more robust methodology.
published_date 2025-03-01T08:22:31Z
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