Ready for regulatory use: NAMs and NGRA for chemical safety assurance

Abstract

New Approach Methodologies (NAMs) that do not use experimental animals are, in certain settings, entirely appropriate for assuring the safety of chemical ingredients, although regulatory adoption has been slow. In this opinion article we discuss how scientific advances that utilize NAMs to certify systemic safety are available now and merit broader acceptance within the framework of Next Generation Risk Assessments (NGRA). Introduction to the advancementsThe science of assuring the safe use of chemicals in products for the consumers who use them and the people in factories who work with them, has advanced a great deal since the 1950s when the only tools for determining the safety of chemicals were experimental animals. Over the intervening decades, an inexorable scientific progression has taken place, towards the elimination of animal testing in chemical safety assessments and the introduction of advances from biomedical sciences to focus on better protecting human and environmental health. During the 1980s and 1990s considerable investment into 'alternatives to animal testing' resulted in the development of several new tests for topical toxicity that could reliably predict the results of animal tests. A regulatory framework then grew around the animal tests and these newer 'animal replacements'.The pace of change has, however, recently quickened as advanced methodologies, that can characterize fundamental biological alterations, have been evaluated and implemented in toxicology in a concerted effort to assure safety in a more human-focused and more exposure-relevant way. A key landmark precipitating the change was the publication of the principles outlined in 'Toxicity Testing in the 21 st Century: A Vision and a Strategy' from the National Academy of Sciences and National Research Council of the USA (NRC, 2007). The book opened the door to a new paradigm whereby advances that have been made in systems biology and associated computational modelling, could be used to transform toxicity testing from its historical animal test base to one founded on in vitro and in silico methods that evaluate pathway changes in cells of human origin. Today, many industry, academic and regulatory toxicologists involved in this evolution face a decision point: whether to adopt these new ways, evaluate their use and seek to improve them, or remain wedded to using traditional animal tests (with the associated ethical and scientific issues they pose in modern society). This decision on whether to adopt or not, occurs against the backdrop of generally slow uptake from regulatory agencies in many geographies, that make it difficult to allow such a transition. Indeed, new approach methodologies (NAMs 1 ), which are increasingly used to assure consumer safety of chemicals in cosmetics (SCCS, 2021;Bernauer, et al., 2021;Dent et al., 2018 and, are generally not yet recognized as a valid route to provide the regulatory safety data in many cases, e.g., to fulfil REACH information requirements for occupational and environmental safety, of the s...

The 19th FRAME Annual Lecture, November 2022: Safer Chemicals and Sustainable Innovation Will Be Achieved by Regulatory Use of Modern Safety Science, Not by More Animal Testing

“…The work conducted over the following 15+ years built strong foundations for the non-animal scientific approaches that we now use in Unilever’s NGRA-based decision-making on consumer and environmental safety of the ingredients used in Unilever products (Figure 1). 5

Figure 1.Next Generation Risk Assessment (NGRA) approaches enable the integration of non-animal data for decisions on the safety of chemicals used in cosmetics and other consumer products. In NGRA-based human health risk assessment, a key metric is the Bioactivity–Exposure Ratio (BER).

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“…The work conducted over the following 15+ years built strong foundations for the non-animal scientific approaches that we now use in Unilever's NGRA-based decision-making on consumer and environmental safety of the ingredients used in Unilever products (Figure 1). 5 The biggest positive impact in re-thinking traditional animal-based safety approaches resulted from the publication in 2007 of the US National Research Council's report on Toxicity testing in the 21st century. 6 This stimulated long-term strategic investment by the US Environmental Protection Agency (EPA) and other US government authorities, and has translated into strong global leadership on New Approach Methodologies (NAMs) by the USA.…”

New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs

“…Given the large number of existing PFASs and the lack of in vivo toxicity data for the majority of the congeners, application of novel approach methodologies (NAMs), combined with information on (estimated) exposure, may assist in their toxicological screening and prioritization for further hazard assessment. NAMs are emerging tools in chemical risk assessment, which include in vitro approaches and in silico approaches or combinations thereof ( Ball et al, 2022 ; Carmichael et al, 2022 ; Dent et al, 2021 ; Punt et al, 2020 ). For the case of PFASs, in vitro toxicity readouts to build such NAMs may be obtained from studies with human hepatocytes or liver cell lines, considering their potential for causing hepatotoxicity and the liver playing a fundamental role in the regulation of cholesterol and lipid homeostasis.…”

A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species

“…NAMs include in vitro methods to study the biotransformation of chemicals, but these generally require primary animal material and can be expensive for large-scale analysis due to, for example, the extensive chemical analytical measurements required. NAMs also include a variety of non-testing approaches, including computational methodologies, with increasing use in the evaluation of chemical safety and, more generally, within the framework of next-generation risk assessments [ 13 ]. Regarding in silico biotransformation studies, 3D molecular modelling techniques have already been applied to study the biotransformation of small molecules by CYPs, providing a useful means of distinguishing substrates from non-substrates [ 14 , 15 , 16 ].…”