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

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). In 2016 the Organisation of Economic Cooperation and Development (OECD) established an expert group to address the development of an integrated approach to the testing and assessment (IATA) of NGTxC, with the objective of addressing this gap. 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, 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 best scoring assays for each IATA module for further validation, for OECD test guideline development, and for their integration in a NGTxC IATA to better identify carcinogens and reduce public health hazards.

JACOBS Miriam;  COLACCI Annamaria;  CORVI Raffaella;  VACCARI Monica;  AGUILA Cecilia;  CORVARO Marco;  DELRUE Nathalie;  DESAULNIERS Daniel;  ERTYCH Norman;  JACOBS A;  LUIJTEN Mirjam;  MADIA Federica Anna Carla;  NISHIKAWA Akiyoshi;  OGAWA K.;  OHMORI Kiyomi;  PAPARELLA Martin;  SHARMA A.K.;  VASSEUR Paule; 

2020-10-19

SPRINGER HEIDELBERG

JRC117908

0340-5761 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC117908,   

10.1007/s00204-020-02784-5 (online),