Present day genetic toxicity testing looks different than it did 20 years ago. The chapter dedicated to this topic in Comprehensive Toxicology has been revised with a focus on genotoxic mechanisms. In addition to identifying mutagenicity, aneugenicity, and clastogenicity, new approach methods also can troubleshoot potentially misleading in vitro positive test results during product stewardship.

Current Regulatory Testing Battery

When assessing product safety the initial genotoxicity battery of tests were selected to ensure detection of all genotoxicants. This conservative approach includes bacterial and mammalian cell assays with most sectors also assessing micronucleus (MN) induction in vivo. While sensitivity of this battery is very high, non-DNA reactive mechanisms of action may induce misleading positive test results in vitro, that are not recapitulated in vivo at human relevant exposures. As regulatory paradigms evolved, and animal testing has come under ethical scrutiny, some sectors advocate for integrating in vivo MN assessment into larger toxicology studies (e.g., ICH S2R1) or have designed in vitro only approaches (SCCS, 2021). For these reasons, many NAMs focus on reporting DNA reactivity or provide evidence for other non-DNA reactive MOAs.

The New Approach Method (NAM), ToxTracker

ToxTracker is a NAM that can identify in vivo genotoxicants with ~90% accuracy, while reporting on oxidative and ER stressors that induce misleading positive test results in vitro. The added specificity of this NAM facilitates its use in animal free testing paradigms (Thakkur et al., 2023) and will soon have an OECD test guideline which will broaden its regulatory use. In this revised chapter, ToxTracker, and other widely used genotoxicity NAMs are highlighted, with advice on when to incorporate them into your genotoxicity testing strategy.

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