Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens

Miriam N. Jacobs*, Annamaria Colacci, Raffaella Corvi, Monica Vaccari, M. Cecilia Aguila, Marco Corvaro, Nathalie Delrue, Daniel Desaulniers, Norman Ertych, Abigail Jacobs, Mirjam Luijten, Federica Madia, Akiyoshi Nishikawa, Kumiko Ogawa, Kiyomi Ohmori, Martin Paparella, Anoop Kumar Sharma, Paule Vasseur

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

While regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests (which include mutagenicity assays). If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, but under most chemical regulations (except plant protection, biocides, pharmaceuticals), this is rare. The decision to conduct further testing based on genotoxicity test outcomes creates a regulatory gap for the identification of non-genotoxic carcinogens (NGTxC). With the objective of addressing this gap, in 2016, the Organization of Economic Cooperation and Development (OECD) established an expert group to develop an integrated approach to the testing and assessment (IATA) of NGTxC. Through that work, a definition of NGTxC in a regulatory context was agreed. Using the adverse outcome pathway (AOP) concept, various cancer models were developed, and overarching mechanisms and modes of action were identified. After further refining and structuring with respect to the common hallmarks of cancer and knowing that NGTxC act through a large variety of specific mechanisms, with cell proliferation commonly being a unifying element, it became evident that a panel of tests covering multiple biological traits will be needed to populate the IATA. Consequently, in addition to literature and database investigation, the OECD opened a call for relevant assays in 2018 to receive suggestions. Here, we report on the definition of NGTxC, on the development of the overarching NGTxC IATA, and on the development of ranking parameters to evaluate the assays. Ultimately the intent is to select the best scoring assays for integration in an NGTxC IATA to better identify carcinogens and reduce public health hazards.

Original languageEnglish
Pages (from-to)2899-2923
Number of pages25
JournalArchives of Toxicology
Volume94
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Bibliographical note

Funding Information:
Publication costs of this paper were funded in full by Public Health England Toxicology Department as part of its continued support for the OECD and leadership of this work by Miriam N. Jacobs. Anoop Kumar Sharma’s participation in this work is funded by the Danish Environmental Protection Agency. Martin Paparella’s participation in this work is funded by the Austrian Federal Ministry for Sustainability and Tourism, Department V/5 Chemicals Policy and Biocides. Akiyoshi Nishikawa, Kiyomi Ohmori and Kumiko Ogawa’s participation in this work is funded by the Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan. Mirjam Luijten’s participation in this work is funded by the Dutch Ministry of Health, Welfare and Sports. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Christian Strupp (Gowanco) and Yong Moon Lee (Chungbuk National University, S Korea) are gratefully acknowledged for their participation in this work. In addition, critical (regulatory) review of a later version of the draft manuscript by Betty C Hakkert, RIVM is gratefully acknowledged.

Funding Information:
Publication costs of this paper were funded in full by Public Health England Toxicology Department as part of its continued support for the OECD and leadership of this work by Miriam N. Jacobs. Anoop Kumar Sharma?s participation in this work is funded by the Danish Environmental Protection Agency. Martin Paparella?s participation in this work is funded by the Austrian Federal Ministry for Sustainability and Tourism, Department V/5 Chemicals Policy and Biocides. Akiyoshi Nishikawa, Kiyomi Ohmori and Kumiko Ogawa?s participation in this work is funded by?the Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan. Mirjam Luijten?s participation in this work is funded by the Dutch Ministry of Health, Welfare and Sports. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Christian Strupp (Gowanco) and Yong Moon Lee (Chungbuk National University, S Korea) are gratefully acknowledged for their participation in this work. In addition, critical (regulatory) review of a later version of the draft manuscript by Betty C Hakkert, RIVM is gratefully acknowledged.

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • Cancer hallmarks
  • Cancer microenvironment
  • Cancer model
  • Cancer prevention
  • Hazard assessment
  • IATA
  • Integrated approaches to testing and assessment
  • Non-genotoxic carcinogenicity

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