Abstract
Although 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. If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, which allows the detection of non-genotoxic carcinogens (NGTxC). However, under most chemical regulations the cancer bioassay is rarely requested, specific requests to obtain information on non-genotoxic mechanisms of carcinogenicity are few, and there are no OECD approved screening methods. When the in vitro genotoxicity battery is negative, usually no further carcinogenicity testing is requested. Consequently NGTxC might remain unidentified and therefore the risks they may pose to human health will not be managed. In contrast to genotoxic carcinogens NGTxCact through a large variety of specific mechanisms, and a panel of tests covering multiple biological traits will be needed. The development of an Integrated Approach to Testing and Assessment (IATA) of NGTxC could assist regulatory decision makers. We examine what NGTxC are and discuss chemical regulatory requirements and limitations. With a strong drive to reduce animal testing and costs in mind, it is essential that proper and robust alternatives for animal testing (3Rs) methods for addressing non-genotoxic modes of action are developed and used. Therefore relevant in vitro mechanisms and assays are described and tentatively organized in levels of information, indicating both a possible structure of the future IATA for NGTxC and associated OECD Test Guideline development priorities.
Highlights
The current thinking is that there are three main stages of carcinogenicity: initiation, promotion and progression, and that the mechanisms by which chemicals cause carcinogenicity can fall into two broad categories: genotoxic and non-genotoxic
From the list of chemicals that are considered as NGTx hepatocarcinogens by International Agency for Research on Cancer (IARC) (Tab. 5), with the Table 1 overview of key non-genotoxic carcinogens (NGTxC) mechanisms and the liver tumor model shown in Figure 3, it may be helpful to consider actual chemical examples that demonstrate how the results from in vitro tests at different levels may contribute to overcome the uncertainties related to in vivo results
Whilst there have been valuable efforts at the international level to validate in vitro assays proposed to start to address this important discrepancy, these have not been wholly successful for a number of reasons, including a lack of mechanistic understanding and difficulties in defining how to meaningfully apply individual in vitro tests, such as the Cell Transformation Assays, for NGTxC assessment
Summary
The current thinking is that there are three main stages of carcinogenicity: initiation, promotion and progression, and that the mechanisms by which chemicals cause carcinogenicity can fall into two broad categories: genotoxic (a mechanism causing initiation) and non-genotoxic (including both initiation and propagation phases). Genetic instability and chronic inflammation underlie these hallmarks, as do epigenetic perturbation mechanisms, changes in DNA methylation (Moggs et al, 2004; Thomson et al, 2012, 2014; Miousse et al, 2015), see Figure 1 Whilst this evolving somatic mutation theory of cancer is widely but not universally accepted (Sonnenschein and Soto, 2013), it provides a useful grouping format to assist with the clustering of relevant assays for the biological processes associated with cancer initiation, promotion/progression, and tumor formation for regulatory test method development and integrated approaches to testing and assessment (IATA) purposes. Relevant in vitro assays are briefly described such that, with respect to the 3Rs test methods and assessment strategies, relevant in vitro Organisation for Economic Cooperation and Development (OECD) Test Guideline (TG) development for chemical hazard assessment will be stimulated
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