New approach methodologies as first tier in an integrated approach to testing and assessment for non-genotoxic...

Assessment of the carcinogenic potential of chemicals is considered an important element of human health risk assessment. However, the approaches currently used for different regulatory sectors have some shortcomings. To overcome these, an alternative testing strategy, like an IATA (Integrated Approach to Testing and Assessment), for the detection of non-genotoxic carcinogens (NGTXCs) is in demand. Such an IATA should be mechanism-based and, wherever possible, consist of New Approach Methodologies (NAMs) to avoid testing in experimental animals. To explore which type of NAMs (in silico and in vitro) should be included in the first tier of an IATA for NGTXCs we performed a case study, in line with various international initiatives focusing on this need. The case study comprised a diverse set of 29 chemicals that together cover different modes of action relevant for non-genotoxic carcinogenesis. Different NAMs, including in silico tools (e.g., QSARS, ADME predictions) and high-throughput in vitro assays such as ToxCast and CALUX, were explored. The findings from the case study reveal the complementarity of the NAMs studied as well as the need for additional NAMs to be included, to ensure a broader coverage of MOAs relevant for carcinogenicity. As such, the case study nicely contributes to a more defined composition of a first tier for an IATA for NGTXC.