enable more accurate simulations of human biology, often resulting in more reliable and human-relevant data without the need for animal subjects.
Unlike classical high-dose toxicity testing on animals, which focuses on observable outcomes( apical endpoints) such as mortality, reproductive failure or organ toxicity, NAMs provide insight into how chemicals disrupt biomolecular processes. Breakthroughs in gene regulation and cell signalling are continuously refining our understanding of these intricate processes, paving the way for more precise and predictive models.
NAMs are also well suited to support existing strategies for filling data gaps, such as chemical grouping and read-across. These approaches allow for data extrapolation based on structural and functional similarities between analogous(‘ source’) substances facilitating the prediction of properties of‘ target’ substances or a common metabolite.
For example, a robust hypothesisdriven justification for using readacross must be provided to fulfil legal requirements under EU REACH. In this context, NAMs can provide mechanistic insights, such as a shared Mode of Action( a biologically plausible series of key events leading to an effect), and offer toxicokinetic information strengthening the readacross justification.
Good, but …?
While the benefits of NAMs are clear, their adoption into regulatory frameworks has been slow. Public pressure and ethical demands on companies and regulatory bodies to adopt alternatives to animal testing have generated a strong push toward reducing the number of animals and improving their conditions during testing.
The 2013 EU ban on the marketing of cosmetics ingredients tested on animals under the Cosmetics Regulation encouraged the development and validation of alternative testing methods, as industries were required to find reliable ways of ensuring the safety of cosmetic products and ingredients without using animals. However, REACH still relies heavily on animal testing.
This regulatory contradiction puts companies in a difficult position, as they must comply with both laws while striving to meet ethical and consumer demands for cruelty-free products, making full compliance without animal testing a continuing challenge.
The European Commission has set the ambitious goal of phasing out animal testing in chemical safety assessments, as outlined in its 2024 roadmap. 7 However, under REACH, only a limited number of endpoints including skin and eye irritation, skin sensitisation, and, to some extent, genotoxicity have been fully accepted for replacement with nonanimal methods.
Despite the growing number of scientific advances, advocates of animal experimentation frequently dismiss non-animal research methods, claiming they lack proper validation. Ironically, animal testing itself has never undergone formal validation. Its continued use is primarily based on historical precedence rather than a rigorous scientific evaluation of their predictive accuracy for human responses.
In contrast, the path to securing regulatory acceptance of NAMs is a rigorous process, requiring strict compliance with the precise standards set by ECVAM and the OECD to ensure reliability and reproducibility. 8 Fortunately, ongoing scientific progress continues to demonstrate the effectiveness of non-animal approaches, leading to a growing number of validated testing methods, as reflected in the expanding TSAR database. 9
However, while validation is essential in building trust and ensuring that human and environmental safety remains paramount, the process is long and complex, involving several welldefined stages and review by various committees. The exponential growth of technology in the field of NAMs over the past two decades, contrasted with the slow progress in implementing the 3Rs suggests that the key challenge is no longer the absence of alternative methods but rather the need for regulatory processes and decisions to keep pace with scientific advances.
NAMs are being developed in part to minimise animal testing
A changing regulatory landscape?
Various regulatory models exist for managing chemical risks, each offering different opportunities for implementing NAMs, depending on the context of use and the structure of the legal framework. In the EU and
50 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981