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Permitted daily exposure limits for noteworthy N-nitrosamines

George Johnson Orcid Logo, Krista Dobo, Bhaskar Gollapudi, Jim Harvey, Julia Kenny, Michelle Kenyon, Anthony Lynch, Sheroy Minocherhomji, John Nicolette, Veronique Thybaud, Ryan Wheeldon, Andreas Zeller

Environmental and Molecular Mutagenesis, Volume: 62, Issue: 5, Pages: 293 - 305

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1002/em.22446

Abstract

A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N-nitrosamines, such as N-nitrosodiethylamine (NDEA), were later detected in other sartan products. N-nitrosamines are pro-mutagens that can react with DNA following...

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Published in: Environmental and Molecular Mutagenesis
ISSN: 0893-6692 1098-2280
Published: Wiley 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57040
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The adducts can result in DNA replication miscoding errors leading to GC&gt;AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA-methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error-free fashion and this can result in nonlinear dose responses and a point of departure or &#x201C;practical threshold&#x201D; for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 &#x3BC;g/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04&#x2009;&#x3BC;g/person/day. Both PDEs are higher than the acceptable daily intake values (96&#x2009;ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. 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spelling 2022-11-02T11:24:41.2276147 v2 57040 2021-06-07 Permitted daily exposure limits for noteworthy N-nitrosamines 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2021-06-07 BMS A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N-nitrosamines, such as N-nitrosodiethylamine (NDEA), were later detected in other sartan products. N-nitrosamines are pro-mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6-alkyl-guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA-methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error-free fashion and this can result in nonlinear dose responses and a point of departure or “practical threshold” for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench-mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans. Journal Article Environmental and Molecular Mutagenesis 62 5 293 305 Wiley 0893-6692 1098-2280 BMD, impurity, linear, nitrosamine, PDE, sartan 16 6 2021 2021-06-16 10.1002/em.22446 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University SU Library paid the OA fee (TA Institutional Deal) Baxter International Inc., Open Access courtesy of Swansea University. 2022-11-02T11:24:41.2276147 2021-06-07T10:02:02.9479587 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine George Johnson 0000-0001-5643-9942 1 Krista Dobo 2 Bhaskar Gollapudi 3 Jim Harvey 4 Julia Kenny 5 Michelle Kenyon 6 Anthony Lynch 7 Sheroy Minocherhomji 8 John Nicolette 9 Veronique Thybaud 10 Ryan Wheeldon 11 Andreas Zeller 12 57040__20182__5b8a3e40de1a4069a1b66cde0c029367.pdf 57040.VOR.pdf 2021-06-16T17:01:12.8337546 Output 2199826 application/pdf Version of Record true This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. true eng http://creativecommons.org/licenses/by/4.0/
title Permitted daily exposure limits for noteworthy N-nitrosamines
spellingShingle Permitted daily exposure limits for noteworthy N-nitrosamines
George Johnson
title_short Permitted daily exposure limits for noteworthy N-nitrosamines
title_full Permitted daily exposure limits for noteworthy N-nitrosamines
title_fullStr Permitted daily exposure limits for noteworthy N-nitrosamines
title_full_unstemmed Permitted daily exposure limits for noteworthy N-nitrosamines
title_sort Permitted daily exposure limits for noteworthy N-nitrosamines
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 George Johnson
Krista Dobo
Bhaskar Gollapudi
Jim Harvey
Julia Kenny
Michelle Kenyon
Anthony Lynch
Sheroy Minocherhomji
John Nicolette
Veronique Thybaud
Ryan Wheeldon
Andreas Zeller
format Journal article
container_title Environmental and Molecular Mutagenesis
container_volume 62
container_issue 5
container_start_page 293
publishDate 2021
institution Swansea University
issn 0893-6692
1098-2280
doi_str_mv 10.1002/em.22446
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N-nitrosamines, such as N-nitrosodiethylamine (NDEA), were later detected in other sartan products. N-nitrosamines are pro-mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6-alkyl-guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA-methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error-free fashion and this can result in nonlinear dose responses and a point of departure or “practical threshold” for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench-mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans.
published_date 2021-06-16T04:12:28Z
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