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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage

Jonathan Fine Orcid Logo, Leonardo Allain Orcid Logo, Joerg Schlingemann Orcid Logo, David J. Ponting Orcid Logo, Robert Thomas Orcid Logo, George Johnson Orcid Logo

Regulatory Toxicology and Pharmacology, Volume: 145, Start page: 105505

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1016/j.yrtph.2023.105505

Abstract

N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we...

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Published in: Regulatory Toxicology and Pharmacology
ISSN: 0273-2300
Published: Elsevier BV 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa65938
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spelling v2 65938 2024-04-03 Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2024-04-03 MEDS N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we demonstrate that AIs that are not experimentally derived for a specific compound, but via statistical extrapolation or read across to a suitable analog, should be expressed on a molar scale or corrected for the target substance's molecular weight. This would account for the mechanistic aspect that each nitroso group can, at maximum, account for a single DNA mutation and the number of molecules per mass unit is proportional to the molecular weight (MW). In this regard we have re-calculated the EMA 18 ng/day regulatory default AI for unknown nitrosamines on a molar scale and propose a revised default AI of 163 pmol/day. In addition, we provide MW-corrected AIs for those nitrosamine drug substance related impurities (NDSRIs) for which EMA has pre-assigned AIs by read-across. Regulatory acceptance of this fundamental scientific tenet would allow one to derive nitrosamine limits for NDSRIs that both meet the health-protection goals and are technically feasible. Journal Article Regulatory Toxicology and Pharmacology 145 105505 Elsevier BV 0273-2300 Nitrosamines; N-Nitrosamine; NDSRIs; Risk assessment; Acceptable intake; Read-across; Carcinogenicity; Percentile; TD50; Toxicology; 18 ng AI default; ICH M7 cohort of concern 1 12 2023 2023-12-01 10.1016/j.yrtph.2023.105505 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. All authors are employed by their respective affiliations. 2024-05-29T16:35:23.2604450 2024-04-03T14:14:57.1719253 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Jonathan Fine 0000-0002-3685-8581 1 Leonardo Allain 0000-0001-6083-9519 2 Joerg Schlingemann 0000-0003-4799-1086 3 David J. Ponting 0000-0001-6840-2629 4 Robert Thomas 0000-0003-0261-8720 5 George Johnson 0000-0001-5643-9942 6 65938__29961__461fe2babfb642e08fd78ab480fd8642.pdf 65938.pdf 2024-04-09T14:58:48.0603502 Output 2087805 application/pdf Version of Record true This is an open access article under the CC BY-NC-ND license. true eng https://creativecommons.org/licenses/by/4.0/
title Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
spellingShingle Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
George Johnson
title_short Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
title_full Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
title_fullStr Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
title_full_unstemmed Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
title_sort Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 Jonathan Fine
Leonardo Allain
Joerg Schlingemann
David J. Ponting
Robert Thomas
George Johnson
format Journal article
container_title Regulatory Toxicology and Pharmacology
container_volume 145
container_start_page 105505
publishDate 2023
institution Swansea University
issn 0273-2300
doi_str_mv 10.1016/j.yrtph.2023.105505
publisher Elsevier BV
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
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description N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we demonstrate that AIs that are not experimentally derived for a specific compound, but via statistical extrapolation or read across to a suitable analog, should be expressed on a molar scale or corrected for the target substance's molecular weight. This would account for the mechanistic aspect that each nitroso group can, at maximum, account for a single DNA mutation and the number of molecules per mass unit is proportional to the molecular weight (MW). In this regard we have re-calculated the EMA 18 ng/day regulatory default AI for unknown nitrosamines on a molar scale and propose a revised default AI of 163 pmol/day. In addition, we provide MW-corrected AIs for those nitrosamine drug substance related impurities (NDSRIs) for which EMA has pre-assigned AIs by read-across. Regulatory acceptance of this fundamental scientific tenet would allow one to derive nitrosamine limits for NDSRIs that both meet the health-protection goals and are technically feasible.
published_date 2023-12-01T16:35:21Z
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