Leadscope, Inc. (an Instem company), in collaboration with Lhasa Limited are leading a working group of pharmaceutical toxicologists and consultants investigating the carcinogenic potency and structure-activity relationships of N-nitrosamines. This is in response to the recent discovery of N-nitrosamines in marketed pharmaceuticals and the regulatory changes that have resulted. The working group is run by Leadscope’s VP of Product Engineering Dr. Kevin Cross and Lhasa Limited Senior Scientist Dr. David Ponting.

Key points in the current regulatory environment, from the point of view of Leadscope customers and Lhasa Limited members, have been driven by the European Medicines Agency (EMA)1 and U.S. FDA2. They are: N-nitrosamine compounds, being potent mutagens and carcinogens, must be controlled to an exposure limit of 18 ng/day, unless there is a close structural analogue with reliable carcinogenicity data. The working group has several topics under consideration as a result:

  • What mechanism(s), in addition to the main alpha-carbon hydroxylation mechanism that leads to potent carcinogenic response, may occur?
  • Which compounds have reliable carcinogenicity data that can be read-across to, and what is the best potency estimate we can derive for those compounds by meta-analysis of all available data?
  • How should the best read-across analog for a novel N-nitrosamine be selected?
  • If there is no single read-across analog with sufficient data, can a combination of analogs give sufficient information?
  • Are there any compounds or substructures where clear toxicity and mechanistic information indicates that the cohort of concern limits may not be applicable?
  • What improvements can we make to the structure-activity relationships for N-nitrosamines?

Ultimately, the working group is writing a series of papers on these topics, so that the expertise developed and shared within the group becomes the foundation for consistent analysis of N-nitrosamines both within the workgroup membership and more broadly. If you have any unpublished carcinogenicity or mutagenicity data for N-nitrosamines that could be useful for the working group, please get in touch with Kevin Cross (kcross@leadscope.com).


1 https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities

2 https://www.fda.gov/media/141720/download

Published by Glenn Myatt

Glenn J. Myatt is the co-founder of Leadscope and currently Senior Vice President, In Silico & Translational Science Solutions at Instem with over 30 years’ experience in computational chemistry/toxicology. He holds a Bachelor of Science degree in Computing, a Master of Science degree in Artificial Intelligence and a Ph.D. in Chemoinformatics. He has published 37 papers, 11 book chapters and three books.