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Permitted daily exposure limits for noteworthy N-nitrosamines / George Johnson, 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

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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa57040
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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 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.
Keywords: BMD, impurity, linear, nitrosamine, PDE, sartan
College: Swansea University Medical School
Funders: Baxter International Inc., Open Access courtesy of Swansea University.
Issue: 5
Start Page: 293
End Page: 305