Establishing a NexGen, mechanism-based environmental risk assessment paradigm shift: Are we ready yet?

Traditional (eco)toxicology has reached a tipping point, with the historical reliance on animal tests for assessing safety being rapidly superseded by the quest for alternative approaches that take advantage of the latest science. These new approaches offer a huge opportunity for increased relevance, biological coverage, and throughput to improve environmental and human health safety assessments, while in parallel addressing growing regulatory and societal calls for increased ethical considerations in the conduct of these assessments. Such public awareness is exemplified by over 1.2 million signatures on the European citizens' initiative (ECI) “Save Cruelty Free Cosmetics—Commit to a Europe Without Animal Testing” (Cruelty Free Europe, 2022; Cruelty Free International, 2023). This demonstration of a clear and strong ethical desire to move away from animal-based testing has galvanized thinking on how to make best use of the latest scientific knowledge anchoring the development of new state-of-the-art science-based approaches to better inform both environmental and human safety decisions. Furthermore, designing products that society trusts, built upon scientific knowledge, is a key pillar of any relevant sustainable innovation program. It is, therefore, ever more important to keep evolving the science to facilitate safe decision-making at pace to fully meet societal and economic needs. Recent developments in New Approach Methodologies, commonly referred to as NAMs, mean that non-animal alternative options, including in chemico, in silico, and in vitro, are becoming readily available to support this change in paradigm (Carmichael et al., 2022). Nevertheless, there is a disconnect between scientific development and regulatory acceptance in some spaces. In actual fact, although the use of recent developments in NAMs has been recognized by the European Commission's Scientific Committee on Consumer Safety (2021), their permitted use within chemicals regulation is restricted. For instance, while the EU Chemicals Regulation (REACH) Annex XI lists several non-animal-based approaches as suitable alternatives, there is in practice limited evidence of their acceptance. In the context of the EU Green Deal, the Chemicals Strategy for Sustainability (CSS) sets further ambitious goals to transform the EU's economy for a more sustainable future by tackling chemical pollution across sources and product life-cycles (European Commission, 2020). Under this scheme, the European Commission is proposing the revision of REACH requirements; introduction of new hazard classes in the regulation on Classification, Labeling, and Packaging of chemicals; and a new framework for the development of chemicals that are safe and sustainable by design (Caldeira et al., 2022). Yet, full implementation of this agenda is very reliant on data availability or generation to fill its requirements. The need to reduce the reliance on animal testing is highlighted as an intrinsic element of the EU CSS, alongside the need to improve the quality, efficiency, and speed of chemical safety assessments. However, if the CSS is implemented within its present hazard-focused regulatory frameworks, it will lead to an increase in the number of animal tests being required, as pointed out by academics, industry bodies, non-governamental organizations, and the European Parliament (Barile et al., 2021; Bridges et al., 2023; Cruelty Free Europe & CEFIC, 2021; Euractiv, 2020), with potentially limited environmental and human health quality gains. It becomes evident that to avoid this dichotomy, the transition to a new way of ensuring chemical safety in the environment requires scientists, eco-toxicologists, risk assessors, regulators, and policy makers to embrace an exposure-led, NAMs-based, Next Generation Environmental Risk Assessment paradigm (Figure 1). At its core, NAMs seek to characterize the hazard potential of new and existing chemicals taking full advantage of batteries of complementary in chemico, in silico, and in vitro methods, to derive a point of departure, comparable to the more traditional “effect level”, which can then be used in conjunction with defined relevant exposure scenarios within environmental risk assessment (ERA) frameworks to characterize safety. Work done by the USEPA has already demonstrated that points of departure obtained using NAMs are, at least, as protective of human safety as the traditional “(not so) golden-standard” in vivo tests (Paul Friedman et al., 2020). It is important to remark that NAMs by their nature offer an in-depth mechanistic understanding of the biological processes underpinning effects. Thus, they allow for a move from the “black-box” approach traditionally taken in eco-toxicology, with obvious benefits as they support the development of knowledge bases to inform future assessments, allowing for evermore efficiency gains. In the context of an exposure-led, evidence-based decision safety framework for ERA, NAMs could play a dual role in supporting new ways of both understanding effects (such as identifying adverse outcomes following biological pathway perturbations) and describing risk (by characterizing protective thresholds without necessarily being predictive of specific toxicity effects) (Kavlock et al., 2018). While exposure assessment is the trigger for further evaluation within a tiered system, NAMs-based approaches would have the added benefit of changing hazard assessment from a standard “one-size-fits-all” safety assessment factor-based approach toward one built on a matrix of effects of chemical classes and species susceptibility. We expect that the development and application of a NAMs-based toolbox will play an increasingly important role in informing the safety of chemicals in the environment, but confidence in the use can only grow if we address five essential elements to establish scientific confidence in NAMs for regulatory use: fitness for purpose, biological relevance, technical characterization, data integrity and transparency, and independent review (van der Zalm et al., 2022). Hence, over the next few years, we anticipate to see an increase in the acceptance of NAMs, catalyzing the integrated use of data, building mechanistic knowledge, and informing chemical screening, prioritization, and safety decisions (Rivetti et al., 2020). We are now at a pivotal decision point in chemical management: foster a transition toward the use of NAMS for environmental safety, anchored on novel knowledge creation, constantly evaluated and translated into regulatorily relevant, fit-for-purpose tools based on the latest advances in science and technology, or remain wedded to using traditional in vivo testing as a basis for ERA, accepting the associated pitfalls, ethical, and practical issues that they pose in modern society. This transition, however, also requires a step change in the design of regulations to ensure that novel science can be used in a much more flexible and adaptative manner, and that scientific knowledge is kept at the core of decision-making. A concerted effort and orchestration between ALL relevant stakeholders (academia, industry, civil society, regulators, and decision makers) remains the foundation for seamless science translation into fit-for-purpose tools for enhanced human and environmental protection. We thank Matthew Dent, Geoff Hodges, Ian Malcomber, Gavin Maxwell, and Carl Westmoreland for providing comments that improved the article. The authors declare no conflicts of interest. Claudia Rivetti: Conceptualization; writing—original draft; writing—review and editing. Bruno Campos: Conceptualization; project administration; writing—review and editing. All authors read and approved the final manuscript.