Elsevier

Computational Toxicology

Volume 20, November 2021, 100186
Computational Toxicology

Developing structure-activity relationships for N-nitrosamine activity

https://doi.org/10.1016/j.comtox.2021.100186Get rights and content
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Highlights

  • N-Nitrosamine carcinogenic potency ranges from extreme to negligible or negative.

  • Specific structural features have clear effects on N-nitrosamine carcinogenic potency.

  • Analysis of N-nitrosamine SAR may require investigation of potentials for metabolism, DNA binding and DNA repair.

  • Presence or absence of structural features can support read-across for novel N-nitrosamines.

Abstract

The detection of N-nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that N-nitrosamine risk assessments be performed on all marketed medical products [EMA/351053/2019 rev 1 (2019)]. Regulation of N-nitrosamine impurity levels in pharmaceutical drug substances and products is described in the ICH M7(R1) guideline where they are referred to as “cohort-of-concern” compounds as several are potent rodent carcinogens [Kroes et. al. 2004]. EMA, U.S. FDA and other regulatory agencies have set provisional acceptable daily intake limits for N-nitrosamines calculated from rodent carcinogenicity TD50 values for experimentally measured N-nitrosamines or the measured TD50 values of close analogs. The class-specific limit can be adjusted based upon a structure activity relationship analysis (SAR) and comparison with analogs having established carcinogenicity data [EMA/369136/2020, (2020)]. To investigate whether improvements in SARs can more accurately predict N-nitrosamine carcinogenic potency, an ad hoc workgroup of 23 companies and universities was established with the goals of addressing several scientific and regulatory issues including: reporting and review of N-nitrosamine mutagenicity and carcinogenicity reaction mechanisms, collection and review of available, public relevant experimental data, development of structure–activity relationships consistent with mechanisms for prediction of N-nitrosamine carcinogenic potency categories, and improved methods for calculating acceptable intake limits for N-nitrosamines based upon mechanistic analogs. Here we describe this collaboration and review our progress to date towards development of mechanistically based structure–activity relationships. We propose improving risk assessment of N-nitrosamines by first establishing the dominant reaction mechanism prior to retrieving an appropriate set of close analogs for use in read-across exercises.

Abbreviations

AI
acceptable intake
ADME
absorption, distribution, metabolism, and elimination
CPDB
Carcinogenicity Potency Database
COC
cohort of concern
EMA
European Medicines Agency
EWG
electron-withdrawing group
FDA
U.S. Food and Drug Administration
LCDB
Lhasa Carcinogenicity Database
NDEA
N-nitrosodiethylamine
NDIPA
N-nitrosodiisopropylamine
NDMA
N-nitrosodimethylamine
NDSBA
N-nitrosdisecbutylamine
NMEA
N-nitrosomethylethylamine
NMNA
N-nitrosomethylneopentylamine
NMIPA
N-nitrosomethylisopropylamine
NMTBA
N-nitrosomethyltertbutylamine
NPDA
N-nitrosodiphenylamine
SAR
structure activity relationship
TD50
dose that results in a 50% excess in tumor incidence

Keywords

Nitrosamine risk assessment
Nitrosamine structure-activity relationships
Structural features supporting read-across for N-nitrosamines
Nitrosamine mutagenicity and carcinogenicity
Computational toxicology
Regulation of nitrosamine impurities

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