A modular strategy for the testing and assessment of non-genotoxic carcinogens

Abstract

A modular strategy is described for the testing and assessment (MoSt) of non-genotoxic carcinogenicity (NGTxC) that is suitable for regulatory applications. It utilizes and builds upon work conducted by the OECD expert group on NGTxC. The approach integrates relevant test methods from the molecular- to cellular- and further to tissue level, many of which have been recently reviewed. Six progressive modules are included in the strategy. Advice is provided for the iterative selection of the next appropriate test method within each step of the strategy. Assessment is completed by a weight of evidence conclusion, which integrates the different streams of modular information. The assessment method gives higher weight to findings that are mechanistically linked with biological relevance to carcinogenesis. With a focus on EU-REACH, and pending upon successful test method validation and acceptance, this will also enable the MoSt for NGTxC to be applied for regulatory purposes across different regulatory jurisdictions.

Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods

“…Thus, the chemicals were selected to provide some overlap, and thus strengthen the mechanistic evidence linking molecular and adverse organ/tissue-level effects and support the development of both Adverse Outcome Pathways (AOPs) and IATAs for metabolic disruption. This approach to chemical selection is being recommended to enhance regulatory relevant development of IATAs and the design of validation studies for the NAMs addressing the IATA KEs ( 238 ).…”