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. Author manuscript; available in PMC: 2025 Jan 31.
Published in final edited form as: Arch Toxicol. 2024 Jun 14;98(8):2299–2308. doi: 10.1007/s00204-024-03802-6

Time for CHANGE: system-level interventions for bringing forward the date of effective use of NAMs in regulatory toxicology

Gro H Mathisen 1, Angela Bearth 1,2, Lowenna B Jones 1,3, Sebastian Hoffmann 4,5, Gunn E Vist 1,6, Heather M Ames 1,6, Trine Husøy 1,7, Camilla Svendsen 1,8, Katya Tsaioun 4, Takao Ashikaga 9, Denise Bloch 10, Aleksandra Cavoski 11, Weihsueh A Chiu 12, Holly G Davies 13, Arianna Giusti 14, Thomas Hartung 15,16, Yoko Hirabayashi 17, Helena T Hogberg 18, Rashmi Joglekar 19, Hajime Kojima 20,21, Kannan Krishnan 22, Seok Kwon 23, Olivia J Osborne 24, Erwin Roggen 25, Andrew A Rooney 26, Christophe Rousselle 27, Jennifer B Sass 28,29, Ovnair Sepai 30, Ulla Simanainen 31, Kristina A Thayer 32, Weida Tong 33, Daniele Wikoff 34, Fred Wright 35, Paul Whaley 1,36
PMCID: PMC11784933  NIHMSID: NIHMS2020232  PMID: 38877155

Introduction

There has been considerable work over the past 20 years designed to bring about a paradigm shift in regulatory toxicology from chemical risk management decisions based on data from animal studies to a “Next Generation Risk Assessments” (NGRAs) system founded on New Approach Methods (NAMs). Whilst all NAM definitions include in silico, in vitro, ex vivo and in chemico approaches (Schmeisser et al. 2023), some also cover in vivo reduction and refinement approaches (ICCVAM 2018; USEPA 2018). The perceived potential benefits of NAMs that are driving the paradigm shift include better protection of humans and the environment, the reduction of animal testing, and ultimately, a faster and more cost-effective test systems for evaluating chemical safety (Dent et al. 2021; USEPA 2014).

In this article, we introduce the “Collaboration to Harmonise the Assessment of Next Generation Evidence (https://vkm.no/english/change/collaborationtoharmonisetheassessmentofnextgenerationevidence.4.46e970eb18cbde223fe711f2.html)”) (CHANGE) project, a new initiative that seeks to design system-level interventions for bringing forward the date of effective use of NAMs, explaining its goals, approach, project management, governance, and funding. CHANGE is far from the first effort to shape the use of NAMs in regulatory toxicology, and we seek to build on or complement efforts by ECHA, EFSA, ICCVAM, NTP, PARC, US EPA, and many others (ECHA 2016, 2023; EFSA et al. 2022; ICCVAM 2018; NTP 2024; PARC 2023; PrecisionTox 2024; USEPA 2018), all of which seek to inform, progress, and advance use and adoption of NAMs.

What makes CHANGE a unique contribution to the challenge of NAM uptake are the following four key approaches being taken to the project, that we expand upon throughout this manuscript:

  1. An emphasis on effective use of NAMs, whereby we do not view the use of NAMs as a goal in itself, rather that there should be an effective regulatory infrastructure enabling effective use of actionable evidence created by NAMs, reflecting the goals and values of the stakeholders that the infrastructure is intended to serve.

  2. A longitudinal, iterated, and interdisciplinary methodology, whereby we seek to explore participants’ experience of the use of NAM data in relation to their goals and use this as data to identify and prioritise areas for possible intervention to promote effective use of NAMs.

  3. A focus on “system factors”, i.e. modifiable elements of the supra-, inter- and intra-organisational structures within which NAM-based research is conducted, interpreted, and acted on, which we believe are under-researched and may provide new opportunities for interventions to bring forward the date of effective use of NAMs in regulatory toxicology.

  4. An ambition of inclusivity and a global outlook, in which we are taking a purposefully cross-sector and international approach to project participation, aiming to cover not only those who create, analyse, and use NAM data (researchers, risk assessors, and risk managers respectively), but also those who are impacted by the decisions taken supported by NAM data (e.g. civil society, workers, communities and others that are impacted by regulatory decisions).

1. Effective use of NAMs

Whilst progress has been substantial, there is a tension relating to the use of NAMs in regulatory toxicology: on the one hand, an impatience to accelerate the phase-out of animal testing in favour of NAMs; on the other, a desire to ensure that NAMs are mature enough to sustain a sufficiently protective risk management infrastructure before more traditional toxicity tests are phased out. For some stakeholders, NAM uptake is too slow. For others, it is too fast. What unites both sides of the NAM use debate are that the regulatory infrastructure for “actionable evidence” created using NAMs should be effective, and that an effective system should be implemented as soon as possible. “Actionable evidence” is transparent, objective, and timely, such that it can reliably support decisions protecting health and the environment from effects of hazardous agents (Chartres et al. 2022). Taking a systems-thinking approach, we aim to identify expected, unexpected, and hidden barriers for a regulatory infrastructure that uses NAM data to be effective, and interventions for breaking down the barriers.

2. Longitudinal, iterated and interdisciplinary methodology

In CHANGE, we seek to specifically focus on system factors as an area of research that could be further developed as it relates to bringing forward the date of effective use of NAMs. By “system factors”, we mean potentially modifiable aspects of the organisational environment in which NAM-based research is conducted, interpreted, and acted on (i.e. covering the process of generating data using NAMs, incorporating these data as evidence in risk assessments, and using risk assessments as a basis for decision-making). We will access the less-observable parts of the regulatory toxicology system (Fig. 1) and design interventions that operate at the system level. The challenge of identifying and addressing these less-observable system factors may explain why they have received less attention than other strategies, such as the validation of NAM-based test methods and the training of different types of actors within the system.

Fig. 1.

Fig. 1

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Illustration of the “iceberg” (Vecteezy.com) of the events and patterns that system participants can observe, from which they develop mental models of the underlying structures of the system [adapted from Kim (1999), Monat and Gannon (2023) and Mosaffa (2023)]. The models can be interrogated by investigators as part of a method for developing theories about how the system works and can be influenced

As part of the CHANGE project, we have developed a specific methodological approach for the identification, prioritisation, and development of interventions that relate to system factors shaping the use of NAMs. We will use qualitative methods in a three-phase approach, with an “iceberg model” of system thinking as the theoretical basis of our methodology. We will use participatory design principles with participants to ensure the results of CHANGE meet stakeholders’ needs and provide a usable end-product.

Iceberg model:

The “Iceberg Model” (Fig. 1) illustrates how less-observable parts support the observable or visible parts of a system [adapted from Kim (1999), Monat and Gannon (2023) and Mosaffa (2023)]. The iceberg model views events and patterns as the directly observable protruding tip of the iceberg, and the structures and systems as indirectly observable. The events are the factors catching our attention, e.g. actions, decisions, and communications. When similar events happen frequently, patterns are recognised from recurring trends (Kim 1999). For the regulatory toxicology system, the observable parts of the system include the toxicity data (typically including animal studies), the risk assessments (formal evaluation of the available data, with conclusions often based on animal studies), and the decisions made by the risk managers (again, historically decisions based on animal studies). Patterns are shaped by the underlying structures, which are factors within the system including physical elements such as equipment and infrastructure, organisational elements such as departments and hierarchies, policy elements such as rules and procedures, ingrained habits such as behaviours and relationships, and the baseline knowledge and approaches acquired through education and training.

Data for informing models of the underlying systems and structures are derived in significant part from interrogating the experiences, perceptions, values, and beliefs of people interacting with the system. Peoples’ reflections on this become “mental models”. The mental models of system participants may be more- or less-developed depending on the extent to which the participants in the system have reflected on their experiences. Mental models can be abstracted and developed through qualitative research methods and will be used to identify system-related barriers to the effective implementation of NAMs and possible interventions to break down the barriers (Fig. 1).

For CHANGE, the iceberg model is interpreted into a three-phase “explore—reflect—design” project, that begins with characterising the mental models of participants (explore), before challenging the models with theory to refine the models of the system (reflect), then finally design system-level interventions that could bring forward the date of effective use of NAMs in regulatory toxicology (design). This approach is presented in Fig. 2 and explained in more detail below the figure.

Fig. 2.

Fig. 2

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The three phases of the CHANGE project

Phase 1: “Explore”.

The first phase of CHANGE is to characterise participants’ mental models of the system. This is based on collecting and then refining anecdotes from participants about their experience of working in the various compartments of the regulatory toxicology system, using group-based elicitation methods. The CHANGE investigators will then analyse the anecdotes for structural themes and potential inhibitors and promotors of effective use of NAMs for further analysis in phase 2.

Phase 2: “Reflect”.

The investigators will convene a multi-disciplinary group of persons with different tasks and roles in the regulatory toxicology system with other relevant disciplines including organisational development, management theory, and practitioners of system thinking to challenge and refine the system models. The group will challenge and refine the draft system models from Phase 1 using the Phase 2 data, additional knowledge of system theory, and their own experiences of working with systems.

Phase 3: “Design”.

The third phase of CHANGE will define and then prioritise, in response to the refined models generated by Phase 2, a set of system-level interventions designed to bring forward the date of effective use of NAMs in regulatory toxicology. These interventions will be summarised and presented to relevant decision-makers as complementary to the many other initiatives aimed at increasing understanding of the complexities around use of NAMs in regulatory toxicology to achieve better protection of humans and the environment.

In the specifics, CHANGE will host three annual workshops (2024, 2025, 2026), each designed to achieve the primary goals of the three-phase, explore-reflect-design project cycle. The workshops will be in-person for the purpose of communication and building trust in what may prove to be a challenging area for discussion, in which people will be encouraged to share candid accounts of both positive and negative experiences of working in the regulatory toxicology system. We believe that this approach will make people aware of the ongoing challenges experienced by different stakeholders and facilitate them to be responsive to each other’s needs. The workshops will be supported by satellite activities as needed, such as on-line workshops that enable participation of people not able to come to in-person events. It is expected that a series of publications and reports will be made available throughout the lifetime of the project. The final deliverable, a White Paper that will detail system-level interventions for bringing forward the date of effective use of NAMs, is expected towards the end of 2026.

3. System factors

A system is “any group of interacting, interrelated, or independent parts that form a complex and unified whole that has a specific purpose” (Kim 1999). “System thinking” focuses holistically on the relationships amongst components of the different levels of the system and makes it possible to identify the underlying structures (Kim 1999; Monat and Gannon 2015, 2023; Mosaffa 2023). System factors are active at multiple levels and typically include people, resources, culture, processes, policies, and legislation.

System’s thinking is an approach to strategic planning that focuses on achieving desirable outcomes by modifying the relationships between the parts of a system, rather than focussing on modifying the parts themselves. This is not to say that the characteristics of the parts are not important for change. Rather, it is a focus on relationships as something that can be modified in addition to other characteristics and therefore provide additional opportunities to intervene for achieving desirable outcomes. For example, improving educational outcomes can be considered both a challenge at the level of the individual (e.g. improving a person’s exam scores through changing a curriculum, teaching techniques, etc.) and a challenge at system level (e.g. the optimum structures for the provision of education, including salaries and other incentives for teachers, physical access to education for rural communities, and other structural issues that may affect the exam scores of individuals in the system). Sometimes parts of a system, such as schools, can be treated as systems themselves.

Thinking at part- and system-level are both important for ensuring that societal goals are achieved. However, system-level factors can be challenging to identify as, unlike the data we use and people we encounter every day, our experience of systems is usually indirect. When we do experience the system itself, it is probably only a very specific part of the system as it interacts with us, rather than one part of the system interacting with another. Without considering system factors, important opportunities for system-level interventions may be overlooked.

Siloing, system-level thinking, and responding to complexity

Organisations in regulatory toxicology, a system that requires many types of specialisations, operate in complex environments. A natural way to deal with complexity is to appoint specialists or create specialist units to do the specific tasks that are needed to respond to various elements of the complex environment, forming silos. This way, experts in respective areas perform tasks in which they are most proficient. In addition, some of these silos were designed to provide a “firewall” to promote objectivity and prevent undue influence, for instance insulating risk assessors from political or economic pressures that may be experienced by risk managers. However, silos may also introduce into the system challenges related to communication across silos and resistance to change (SHRM 2024).

Regulatory toxicology includes several layers of silos. Organisations/institutions within the system are separate silos, there may also be silos within an organisation, and a group of organisations/institutions may constitute a silo.

NAMs are a challenge to the regulatory toxicology system because they potentially introduce a range of accompanying specialisations needed to generate, analyse, and act on NAM data, and a need for adaptation of the regulatory and legislative frameworks. These new specialisations include mechanism-based toxicity models, read-across techniques, predictive and probabilistic risk modelling, artificial intelligence and machine learning, and so forth. These specialisations are added to an already complex set of specialisations relating to economic sector, environmental compartment, chemical class, product categories, and so forth—each with their own perspective, frames, and ways of operating.

In a system that may instinctively create silos to respond to complexity, different types of actions may be needed to manage challenges related to the siloing. In the shorter term, organisations may need to work out how to manage an inevitable skills gap whilst the next generation of employees are being educated and trained. In the medium term, organisations may also need to plan to prevent the excesses of siloing from derailing the uptake of NAMs, if e.g. current recruitment models assume that more specialisation is required than is in fact available. At a higher, supra-organisational level, it may be important to think about how to avert recruitment challenges with e.g. long-term system-level planning around education of high-school aged children, undergraduates, and graduates in such a way that a pipeline of experience and expertise suited to many specialisations is created.

NAMs may introduce sufficient additional complexity to fundamentally threaten the functionality of a silo-oriented system, such that it may even be the case that organisational structures developed for the pre-NAM era of regulatory toxicology system cannot scale with the complexity of the post-NAM environment. If so, the introduction of NAMs could as easily break the regulatory system as improve it, and system-level strategies that can introduce different organisational structures may be required.

Siloing also illustrates how systems impinge on other factors of interest to research projects related to CHANGE. Taking the specific example of human factors, difficulties related to communication and other elements of social contact that can be caused by siloing may contribute to the lack of trust in NAM data that is a recognised barrier for NAM uptake (Čavoški et al. 2024). Such a situation could be improved not only by education, that directly addresses individual confidence with NAM data, but by looking at organisational structures that encourage interpersonal relationships that also have an important role in building trust. Therefore, tackling a tendency towards siloing may offer an additional strategic route to intervening on human factors, providing a more rounded overall strategy for NAM uptake.

We are not yet offering solutions. All we are saying is that siloing is an example of how a system-level, sometimes long-term view could potentially contribute to solve the challenge of effective use of NAMs. The issue cannot be solved overnight, involves human resources and recruitment as much as it does scientists, and education policy as much as it does chemical policy. But system thinking provides for that long view to be considered and broken down strategically: activities can be mapped out over years, assigned to different actors, and strategized around. The methods described below to implement CHANGE are intended to provide an additional layer of thinking and potential range of interventions from which to choose.

4. Inclusive participation and a global outlook

In CHANGE, we categorise regulatory toxicology into four major constituent parts: data generation (the research and testing that generates the primary data for decision-making); data analysis (the evidence review and risk assessment processes that make sense of the primary data for the purpose of decision-making); data use (the policy- and decision-making that uses the analyses of scientific evidence about risk, and other data, for making decisions); and impacts (the direct and indirect effects on the population or environment of policies and decisions).

We are seeking to ensure representatives of groups in each part of the regulatory toxicology system participate in CHANGE, including non-profit, voluntary citizens’ groups which are organized on a local, national, or international level (NGOs), national and international authorities and agencies, industry, and academia, to ensure that all voices are heard, and all experiences accounted for. We aim to include participation of representatives for ongoing initiatives and projects that are approaching the same problem but from different directions and with different assumptions, such as e.g. projects in the Horizon Europe PrecisionTox programme and the Horizon Europe PARC partnership. We also seek to be global, to further promote exchange of experience between traditionally disconnected regions, provide maximum opportunity for cross-pollination of ideas, and to identify interventions that can be adapted or applied in the context of local conditions. Historically, it has been challenging to involve risk managers, NGOs, and participants from low- and middle-income countries and from regions where English is not widely spoken. Whilst we intend to make deliberate outreach efforts to ameliorate these challenges, they will ultimately be limited by resource constraints (e.g. for extensive international travel or live translation).

We hope that the process of co-design in narrative development will ensure individuals within the high-level actor network retain a vested interest in returning year-on-year, whilst co-design is evidenced to be an effective tool for establishing trust and meaningful collaboration in research (Bradwell and Marr 2017; Durose and Richardson 2016).

Project management and governance

An international, interdisciplinary, and cross-sectorial group of actors from the regulatory toxicology community involved in several previous and ongoing projects and initiatives to support the shift towards implementation of NAMs, has been established. The participants are from Asia, Australia, Europe, and the United States, and cover most parts of the regulatory toxicology system, at both the national and international level. The project is managed by the Norwegian Scientific Committee for Food and Environment (VKM) and supported by the Evidence-Based Toxicology Collaboration (EBTC; Johns Hopkins Bloomberg School of Public Health). The participants are organised in a project team and an advisory board. The project team’s responsibility is to implement the project according to the plan. The advisory boards responsibility is giving strategic guidance and support to the project team and sharing information about ongoing projects addressing similar issues to avoid duplication of efforts.

Position of CHANGE in relation to existing initiatives

CHANGE aims to have broad applicability in relation to effects of chemical exposures (e.g. biocidals, food additives, industrial chemicals, pesticides, etc.) on human health and the environment from a wide range of sources (e.g. chemical production and processing, industrial manufacturing, consumer products, food and food packaging, cosmetics and personal care products, etc.) on a range of populations, not overlooking how workers and communities may be exposed through multiple sources.

Several ongoing projects and initiatives are addressing factors that may act as barriers for the shift from a system largely based on in vivo rodent data to a system based more on in vitro, in silico, and other NAM data. These factors include insufficient involvement of the regulatory community, and a number of challenges related to scientific and regulatory readiness and the protective ability of NAMs as actionable evidence for human health and/or environmental risk assessment. These are examples related to the lack of central steering of this shift, uncertainty around legal constraints and the legal defensibility, the need for improvement of policies and practises, validation problems, deficits of the post-validation process, lack of funding for the development and validation of NAMs, time and costs related to the need for expertise and training, lack of familiarity with methods and uncertainty around data interpretation affecting the willingness for rethinking, lack of standardisation of the methods, economic effects, missing interaction with stakeholders, and challenges handling the uncertainty in mechanistic understanding and evidence (Archibald et al. 2015; Bottini et al. 2008; Bottini et al. 2007; Browne et al. 2024; Busquet and Hartung 2017; Čavoški et al. 2024; Chartres et al. 2022; ECHA 2023; Hartung et al. 2013; Hoffmann et al. 2022; ICCVAM 2018; Leist et al. 2012; Maertens et al. 2022; Maertens et al. 2024; Marx-Stoelting et al. 2023; Meigs et al. 2018; National Academies of Sciences and Medicine 2017, 2022, 2023; Pain et al. 2020; USEPA 2021; von Aulock et al. 2022; Vonk et al. 2015).

CHANGE aims to avoid duplication of efforts by actively seeking for collaboration with ongoing projects and initiatives looking into the same problem space. The goal is to build on relevant and ongoing projects and initiatives across the globe, whilst identifying ways to collaborate and integrate the objectives/system-level approach of CHANGE into other projects and research. Thus far, a potential for duplication with three ongoing projects have been identified. These include one PrecisionTox project, one project in the European Partnership for the Assessment of Risk from Chemicals (PARC), and one project at the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) (ICCVAM 2018; PARC 2023; PrecisionTox 2024). Socio-technical barriers that inhibit implementation of NAMs are explored in the PrecisionTox project (Čavoški et al. 2024), a strategic roadmap guiding the uptake of NAMs into the regulatory practise of chemical risk assessment in the EU will be developed in the PARC project, and opportunities for encouraging the consideration of alternative methods are explored in the ICCVAM project. Contact has been established with persons involved in these projects to explore possibilities for collaboration.

Conclusion

Regulatory toxicology is a complex adaptive system of data generation (research and testing), interpretation (evidence review and risk assessment), and impact (decision-making, risk management). System factors are the modifiable elements of how the parts of the system respond to external and internal changes and challenges, including how the parts respond to each other. The general interest in relying more heavily on NAMs disrupts the equilibrium of the traditional risk assessment paradigm, or system, and may cause the individual parts of the system to behave in different ways (some optimal, some sub-optimal).

CHANGE is a 3-year process based on involvement, networking, and dialogue to build cross-system consensus on fundamental system factors preventing the paradigm shift and opportunities for intervention. CHANGE includes an international group of people with different roles and focuses, having different specialisations, working in different sectors with specific types of chemical substances covered by specific legislations. Building on previous and ongoing efforts and initiatives, focussing on system factors, we believe CHANGE can be a catalyst for bringing forward the date of effective use of NAMs in the regulatory toxicology system.

Acknowledgements

We thank Miles Davenport (University of New South Wales) for valuable comments on draft versions of this manuscript.

Funding

The project is funded by the European Food Safety Authority. Gro H. Mathisen, Angela Bearth, Lowenna B. Jones, Gunn E. Vist, Heather M. Ames, Trine Husøy, Camilla Svendsen, and Paul Whaley were supported by European Food Safety Authority. The views expressed reflects only the author’s view, and EFSA is not responsible for any use that may be made of the information it contains.

Footnotes

Conflict of interest The authors declare that they have no conflict of interest. Jennifer B. Sass is on faculty at George Washington University and works for the Natural Resources Defense Council (NRDC), a public interest non-profit group. As a part of her work, she makes public statements on the science, policy, and regulatory actions, including litigation to enforce environmental laws, relevant to the subject matter of this manuscript. Several of the co-authors are currently working on one or more of the EU funded projects PrecisionTox, ONTOX, and PARC (Gro H. Mathisen, Angela Bearth, Gunn E. Vist, Heather M. Ames, Trine Husøy, Camilla Svendsen, Denise Bloch, Aleksandra Čavoški, Thomas Hartung, Erwin Roggen, Christophe Rousselle, Ovnair Sepai, and Paul Whaley).

Disclaimers: The views and opinions expressed by the authors are their own and do not necessarily represent the views or policies of their employers or organizations. The opinions expressed in this paper are those of the authors, and do not necessarily reflect the position of U.S. Food and Drug Administration. The author Kannan Krishnan is employed at California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA). The views are those of the author and do not necessarily reflect the views or policies of OEHHA or California Environmental Protection Agency. The author Kristina Thayer is employed at the U.S. Environmental Protection Agency. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA. Any mention of trade names, products, or services does not imply an endorsement by the U.S. government or the U.S. EPA. The U.S. EPA does not endorse any commercial products, services, or enterprises. The authors Andrew A. Rooney and Helena T. Hogberg are employed at the U.S. National Institute of Environmental Health Sciences. The views expressed in this manuscript are those of the authors and do not necessarily represent the views or policies of the U.S. National Institute of Environmental Health Sciences.

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