‘NAMs’ – Background and definition
What are NAMS?
Over the past decade the term ‘NAMs’ has become a buzzword amongst scientists and organisations promoting the replacement of animal use in research and testing and the term has become more widely used in the scientific community. Yet, there still appears to be no consensus on what ‘NAMs’ actually means. This short briefing looks at the background to the term, its varied (and sometimes conflicting) uses, and discusses how the term is used by the Lush Prize.
What does NAM stand for?
There is general agreement that the acronym stands for ‘New Approach Methodologies’ (or, in the singular, ‘New Approach Methodology’).
The term NAM was apparently coined at a 2016 ECHA (European Chemicals Agency) workshop that produced a document titled ‘New Approach Methodologies in Regulatory Science’.
There are, however, a few diverging definitions:
‘Non-animal methods’ – UK NC3Rs, 3Rs Centre Utrecht and RSPCA (Report, 2024)
‘Novel Alternative Methods’ – National Institutes of Health Advisory Committee
‘New Alternative Methods’ – BDO Market Analysis Report
What actually are NAMs?
This is where agreement begins to diverge.
The ECHA workshop document from 2016 doesn’t provide a firm definition of the term NAM.
The Executive Summary (page 6) states:
“NAMs were taken in a broad context to include in silico approaches, in chemico and in vitro assays, as well as the inclusion of information from the exposure of chemicals in the context of hazard assessment. They also include a variety of new testing tools, such as ‘high-throughput screening’ and ‘high-content methods’ e.g. genomics, proteomics, metabolomics; as well as some ‘conventional’ methods that aim to improve understanding of toxic effects, either through improving toxicokinetic or toxicodynamic knowledge for substances.”
(NB: ‘Conventional methods’ may refer to animal-based research).
It continues:
(Page 8) “the animal testing and the NAMs will be complementary, and not necessarily competing approaches. As such, it is advisable to see how the design and conduct of animal testing could be improved so that it would better inform the development of read-across or weight-of-evidence (WoE) approaches for analogue chemicals…”
(Page 17) “It was discussed that (especially for higher tier endpoints) NAMs are not currently a standalone piece of information for a category and need to be linked to in vivo data. Further, it was suggested that a package of in vivo data with NAMs would be very powerful and could confirm read-across arguments. As such, NAMs are not a disconnected entity, but must be linked to in vivo data. Thus, a well-defined category, anchored to high quality in vivo data and NAMs would confirm the hypothesis of category membership and hence facilitate read-across.”
In the report of a 2023 ECHA NAMs workshop it appears that there was still no agreement on what NAMs are, but it gives reference to a Background Paper where ECHA “provided the following statement as a working definition” (page 6):
“NAMs denote alternatives to traditional toxicity methods that typically involve animal testing. These alternatives are useful for predicting and assessing chemical risks and hazards, by providing mechanistic information for biologically complex endpoints. They include, e.g. in vitro, in chemico methods and in silico computational models, which may be used alone or in combination with other methods and have the potential to be quicker, cheaper and use less animals.”
It continues (page 6):
“The ECHA definition was in-line with the variety of other definitions provided in the workshop. Whilst there were a range of opinions, most speakers and delegates agreed that NAM is a broad term encompassing any methodology, technology or approach providing information on hazard or risk assessment of chemicals that at a minimum contribute to refine, reduce or replace animal testing. All speakers and delegates agreed that NAMs include the use of in silico, in chemico and in vitro approaches. The use of Integrated Approaches to Testing and Assessment (IATA) and Defined Approaches (DA) was also highlighted.”
The main report provides the following in the section ‘Definitions’ (page 5):
“Within the workshop, there was a divergence of opinions with regard to the exact definition of the terms ‘Non-Animal Methods’ or animal-free methods, as well as a distinction between that and ‘New Approach Methodologies’ (NAMs) as some participants considered the latter term may include animal testing. The goal of the roadmap discussed at the workshop is the transition to a regulatory system based on non-animal methods.
Non-animal methods may include NAMs in the short- to medium-term to reduce or refine animal testing. There was no agreement in the workshop on the definition of NAMs or their implementation as non-animal testing methods.”
A report from the 2022 European Partnership for Alternative Approaches to Animal Testing ‘Deep Dive Workshop’ on the use of NAMs in regulatory decisions for chemical safety notes: “The workshop recognised that, as yet, there is no formally accepted definition of the phrase ‘New Approach Methodology’.”
In 2024 a new scientific journal was launched – NAM Journal – describing its purpose as embracing “these recent advancements by serving as a hub for dissemination and worldwide exchange of information regarding state-of-the-art NAM developments.” In its first editorial, it states:
“Although still under debate and subject to interpretation, NAMs generally refer to non-animal approaches, including cell culture (in vitro) and computational (in silico) methods or combinations of those. Ideally, for a new test or assessment method to be considered a NAM, it is relevant for the regulatory hazard or safety assessment of a compound.” (Our emphasis).
According to a 2024 report by the UK’s Department for Environment, Food and Rural Affairs:
“The UK Committee on Toxicity of Chemicals (COT) defines NAMs as New Approach Methodologies including but not limited to high throughput screening and other in vitro assays, omics and in silico computer modelling strategies (for example Artificial Intelligence (AI) and machine learning) for the evaluation of hazard and exposure. […] Although correct, this definition focuses on the technologies involved. The utility of NAMs lies in their function of recording changes occurring within and provoked by biomolecular interactions (with chemical pollutants) that impact biology.”
The European Food Safety Authority, in a 2024 ‘Review of New Approach Methodologies for Application in Risk Assessment of Nanoparticles in the Food and Feed Sector’ proposed the following working definition (page 12):
“Any technology, methodology or approach that can provide useful information to support chemical risk assessment by informing on the hazard […] and exposure of a chemical without the use of animal tests shall be considered a New Approach Methodology (NAM). This includes in silico, in chemico, in vitro, ex vivo and specifically for NMs, also physicochemical characterisation approaches. Any non-animal method can qualify as a NAM when it is validated or when it has been demonstrated to be scientifically valid for application in risk assessment.
In most cases various NAMs have to be applied in combination, usually in frameworks describing tiered approaches, to respond to questions of regulatory relevance. However, any approach modifying an existing animal test would not be considered a NAM per se, even though innovative methods might be applied for this purpose. In line with this, the application of simple whole organisms in vitro models would qualify as NAMs as long as they can provide useful information for risk assessment and/or enable better design of in vivo testing. Animal tests might be included in such frameworks along with NAMs, usually in the higher tiers.” (Our emphasis).
The EFSA definition appears contradictory – it begins by stating NAMs avoid the use of animal tests and ends by including “simple whole organisms”, including “e.g. C. elegans” in the figure that follows the definition. This definition is based on ‘simple whole organisms’ falling outside of the agreed legal definition of an ‘animal’ according to EU Directive 2010/63/EU (Protection of animals used for scientific purposes, see Article 1(3)) and remains a controversial topic of debate, for both ethical and scientific reasons.
Norecopa, Norway’s National Consensus Platform for the advancement of the 3Rs, bases its definition differently:
“A simple way to differentiate the pure definitions of NAMs and NATs [Non-Animal Technologies] is to consider whether the starting-point for development of the method was an animal model or not. NATs are designed to replace animal models, whereas NAMs are more focused on addressing a scientific question, which may then involve the use of in vitro, in silico or in chemico methods, often with human tissue or data.”
A 2024 LinkedIn post on this topic, by Paul Jennings, Editor in Chief of the journal Toxicology in Vitro continued the discussion, leading Jennings to suggest the following definition: “An in vitro and/or in silico method that is developed/used for regulatory purposes.”
Are NAMs restricted to regulatory and safety testing?
In another 2024 LinkedIn post, Maurice Whelan, of the European Commission’s Joint Research Centre, writes (based on the 2016 ECHA workshop discussion):
“For a new test or assessment method to be considered a NAM, it must be relevant for the regulatory hazard or safety assessment of a chemical. Likewise, for a method to become an OECD test guideline, it must have a regulatory purpose. Thus no regulatory relevance or purpose, no NAM!”
He continues:
“I believe that calling something a NAM when it isn’t is misleading to stakeholders and distracts from the pressing need to redesign the regulatory testing-assessment interface so that regulatory assessments can be conducted using actual NAMs.”
However, he concedes:
“The term NAM has ‘escaped’ from the industrial chemicals world and is popping up all over the place, even in discussions about new approaches in biomedical research.”
Ellen Berg, Chief Scientific Officer at Alto Predict, stated in another 2024 LinkedIn post, referring to a National Institutes of Health working group report: “biomedical researchers have adopted the term, sometimes referring to NAMs as ‘Novel Alternative Methods‘ and using the term more broadly to describe “innovative methods, models, and technologies to answer complex questions about human health and disease”.”
The NAM Journal editorial adds to this discussion:
“In recent years, NAMs have also been introduced in other scientific areas and are gaining momentum. This especially holds for, but is not limited to, the biomedical research field. At present, NAMs are used in the biomedical research area for the investigation of mechanisms underlying human disease, the identification of novel diagnostic and prognostic biomarkers and the testing of new therapeutic strategies of various nature.”
As one respondent to Maurice Whelan’s post, Laura Holden of Birmingham University, commented:
“Perhaps the horse has bolted in terms of definitions though – as others have noted, there are many different definitions and so it means different things to different people (the social effects within the technical world). Maybe the only way to contain it / reframe it now is to prefix/suffix, for example, ‘regulatory NAMs.’”
Can NAMs include the use of animals?
It is tempting to use the term NAMs to define research methods that avoid any use of animals whatsoever, but simply desiring that does not make it true.
The 3Rs Centre Utrecht uses NAMS to describe “all methods that do not use laboratory animals, including methods that are not directly aimed at replacing existing laboratory animal use.”
In a 2022 paper published in Frontiers in Toxicology, the authors state:
“NAMs are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment without the use of animals, including in silico, in chemico, in vitro, and ex vivo approaches.”
As already noted, ECHA’s 2016 NAMs workshop suggests (page 8) “animal testing and the NAMs will be complementary, and not necessarily competing approaches.”; (page 17) “…NAMs are not a disconnected entity, but must be linked to in vivo data.” At best this could be seen as Reduction of animal use in research and testing.
At the ECHA 2023 NAMs workshop, Patience Brown of the OECD discussed the OECD’s position on NAMs. She said that New Approach Methods include everything that is not an “old approach”, including in-chemico, in-vitro, data science, computation, “as well as in-vivo methods that fill data gaps”, adding that NAMs are “less resource intensive”, including the use of fewer or no animals.
In 2018 the US Environmental Protection Agency wrote, in a Strategic Plan (page 6):
“The organizing framework for EPA’s strategy to reduce vertebrate animal testing relies heavily on what have been termed new approach methodologies (NAMs). This phrase has been adopted as a broadly descriptive reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment that avoids the use of intact animals” (our emphasis).
The Food and Drug Administration, while noting the use of NAMS “for use in place of traditional animal testing” and as an opportunity to support the 3Rs, adds: ”One such new approach method that CFSAN has been working to develop is the use of C. elegans, a tiny transparent roundworm, as a non-mammalian model to screen for chemicals that may be toxic to mammals.”
(CFSAN: The Center for Food Safety and Applied Nutrition, a branch of the FDA)
The 2024 EFSA review, discussed above, also provides for the use of what it calls “simple whole organisms”, specifically including “e.g. C. elegans”.
The British Toxicology Society includes some animal use in its definition of NAMs, seemingly as a replacement for using mammals. The examples it lists are zebrafish, fruit fly, water flea, round worm and frog.
In response to the Maurice Whelan’s popular LinkedIn discussion, Comité Scientifique Pro Anima replied:
“Using the NAMs acronym for New Approach Methodologies does not clearly state if the methodologies include living animals. […] Using NAMs acronym for New Alternative Methods neither clearly states that it does not involve animals and suggests that the cutting edge methods are meant to be alternative to current in vivo and in vitro ones. These are much more than alternative methods, they have better potential to provide more reliable and more clinically representative answers. Thus, we tend to use non-animal New Approach Methodologies, to clarify that behind the acronym NAMs, there are animal-free human-relevant methods such as 3D in vitro technologies and in silico approaches.”
It appears that NAMs are used to generally refer to methods that avoid the use of non-mammalian species, but not avoiding the use of all animals.
When is ‘New’ no longer new?
The term NAMs appears to date back to 2016 and references test methods that, while continuing to be developed and improved, often date back further. So ‘new’ shouldn’t be seen directly as relating to a specific time but to whether the approach is one that is different to traditional animal testing.
The 2022 paper published in Frontiers in Toxicology, mentioned previously, notes:
“NAMs are not necessarily newly developed methods, rather, it is their application to regulatory decision making or replacement of a conventional testing requirement that is new.”
While the use of the word ‘new’ does not seem particularly helpful and creates some confusion, it is perhaps too late to change it at this stage.
How does the Lush Prize define NAMs?
The term NAMs has embedded itself deeply into the lexicon and discussion around methods to replace the use of animals in research and testing, even if the meaning of NAMs isn’t fully agreed on.
We agree with Dr Laura Holden’s comment that “the horse has bolted in terms of definitions” and that NAMs “means different things to different people”. The term NAMs is here to stay, at least for the immediate future, and this indecision on its meaning provides an opportunity to suggest our own definition, breaking away if necessary from previous attempts.
‘Non-Animal Methods’ and ‘New Approach Methodologies’ are not the same thing; the latter does not necessarily exclude some animal use. Therefore, we need to qualify what we are actually referring to when using the term NAM by adding some additional words whenever the acronym is used. The Comité Scientifique Pro Anima, in response to Maurice Whelan’s LinkedIn post, commented “we tend to use non-animal New Approach Methodologies”, and this clarification makes sense.
Our definition of ‘non-animal’ refers not just to using any live or dead animal but also to not using any animal-derived components (other than immortalised cell lines).
Lush Prize has chosen the following for our communications around NAMs:
1: Short definition:
Non-animal New Approach Methodologies (or: non-animal NAMs)
2: Longer definition:
‘Non-animal New Approach Methodologies’ is a broad term encompassing any methodology, technology or approach that avoids any use of animals including any primary animal-derived components and invertebrates. These include, but are not restricted to, the use of in-silico (computational), in-chemico and in-vitro (cell culture) approaches, existing data or combinations of these.
We are interested in hearing the thoughts of other stakeholders about definitions of NAMs – you can share your thoughts, and tag us, on LinkedIn or Bluesky, or email us.
Also see the Lush Prize report, ’The UK as a leader in new approach methods (NAMs) for safety science’, which describes how the bans on animal tested cosmetics could be used as a framework to phase out all regulatory tests on animals.
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