Challenges and Opportunities in the Development and Adoption of New Approach Methods (NAMs)

At the 2024 Agrochemicals (AGRO) Division of the American Chemistry Society’s fall meeting, virtual and in-person symposia brought together international experts to provide viewpoints on challenges and opportunities to increase the adoption of new approach methodologies (NAMs) in regulatory frameworks. NAMs are generally defined as any technology, methodology, or approach that provides information about chemical hazard and risk assessment and replaces, reduces, or refines animal testing. Key drivers for the transition to NAMs are to reduce animal testing, characterize mechanisms of toxicity, and prioritize where further testing may be needed to inform hazard and risk assessment. NAMs are diverse and can include in silico methods such as quantitative structure–activity relationships (QSARs), omics, read-across, in vitro assays, organoids, and transgenic eleutheroembryonic assays. Despite their rapid development, adoption of NAMs in regulatory frameworks has been relatively slow. This slow transition is due to one or more factors such as adapting relevant legislation, a lengthy validation process, limitations of the context of use, building scientific confidence, and adopting harmonized regulatory test guidelines. This Viewpoint highlights some of the opportunities and challenges presented by the speakers in these symposia to accelerate the development of NAMs, build scientific confidence, achieve societal acceptance, and transition toward greater adoption in regulatory frameworks (Table 1).

Table 1. Opportunities and Challenges to Accelerate the Development of NAMs and Their Transition to Regulatory Adoption.

Scientific Confidence Frameworks (SCFs) and Validation: Validating NAMs is crucial to ensure their reliability and relevance. As an alternative to the traditional validation process, SCFs provide a robust and flexible alternative approach to modernize the validation of NAMs and do not preclude the ability to conduct ring trials when deemed necessary. Whether relevance and reliability are demonstrated under a SCF or traditional validation, following one of these approaches is necessary before a NAM can be confidently used to inform regulatory decision-making without compromising human and environmental safety.

Case Studies: Case studies are critical to demonstrate effectiveness, address uncertainty, and improve regulatory adoption of NAMs. Case studies provide concrete examples of how NAMs can be successfully applied in a specific context, which helps to build confidence and understanding among users and ultimately encourages wider adoption.

Regulatory Acceptance: Advocating for flexible regulatory frameworks, which encourages innovation while ensuring safety, will support regulatory acceptance and the transition to NAMs. Cooperative relationships among the research community, industry, and regulatory agencies are critical for establishing guidelines and standards for increased implementation of NAMs in chemical safety evaluations. A lack of clear guidance from regulatory agencies can create hesitation among researchers and manufacturers to innovate and adopt NAMs for regulatory submissions.

Societal Acceptance: Improving public trust and societal acceptance of NAMs can be achieved through a combination of factors. Some of these factors include highlighting their benefits, education to demystify them to the public, transparent communication by researchers and risk managers with the public to build trust and provide reassurances that protection of humans and the environment will not be comprised, engagement with stakeholders early in the process, publishing results in reputable peer-reviewed scientific journals, and presenting findings at scientific conferences.

Interdisciplinary and Multipartite Collaboration: Building scientific confidence to promote wider adoption and acceptance of NAMs in regulatory decision-making can be achieved by fostering interdisciplinary and multipartite collaborative efforts, significant research investments, maximizing data sharing opportunities, continuing education, addressing knowledge gaps with innovation, sharing large public data sets to enhance the development of predictive models, integration into endorsed adverse outcome pathway (AOP) frameworks, harmonization of protocols, and developing clear guidelines for their use.

Outlook and Research Needs for Wildlife and Endocrine Disruption (ED)

NAMs are being developed for wildlife species to address data gaps for safety evaluations. For example, NAMs for cross-species extrapolation are useful when testing is restricted or prohibited and when addressing concerns regarding federally listed threatened and endangered species. However, for these and related purposes, NAMs must demonstrate relevance and reliability, have defined domains of applicability, and provide documentation of strengths and limitations. These elements are necessary to establish scientific confidence and acceptance of NAMs for cross-species extrapolation. Therefore, fit-for-purpose and collaborative case studies, focused primarily on evaluation and validation and involving developers, users, and regulators, are essential and encouraged for advancing the incorporation of NAMs into standard practice for cross-species extrapolation.

As part of regulatory ED assessments, NAMs can be used to support the identification of endocrine activity that could lead to ED in an intact organism. Such information is valuable for screening and prioritization of chemicals of highest concern. For example, transgenic eleutheroembryo assays can be used to support identification of endocrine activity in nonmammalian species (e.g., OECD test guidelines 248, 250, 251, and 252) and additional eleutheroembryo assays are under development. There is an example for nonmammalian endocrine assessments in which data from an eleutheroembryo assay can be accepted for regulatory purposes under specific conditions in place of generating data in a traditional in vivo endocrine activity screening assay.¹ There is, however, a gap for in silico and in vitro methods based on fish or amphibian biology, though it is not clear whether existing methods based on human biology could be equally informative.

Short-term, key needs center around refining the applicability domains of the available NAMs, improved understanding of ADME (absorption, distribution, metabolism, and excretion) processes to support use of data from NAMs, curation of high-quality in vivo data to help contextualize the results from NAMs, demonstrating where NAMs bring value to assessment processes, and highlighting gaps in knowledge or pathway coverage of available NAMs. In the long term, there is a need to improve our understanding of quantitative linkages between NAM-derived mechanistic data and adverse outcomes and the further development of new technologies (e.g., cell painting, transcriptomics, and organ-on-a-chip) and tools to explore endocrine pathways beyond those currently assessed under regulatory requirements.²

Role of Scientific Confidence Frameworks (SCFs) to Modernize the Validation of NAMs

A limitation of the traditional validation approach used for NAMs (e.g., those used to develop harmonized regulatory guidelines) is that they require ring trials (i.e., “round-robins”) that are time- and resource-intensive. This has led to calls for a more “fit-for-purpose” validation process, which raised the question of how this would be operationalized, as well as concerns of creating a NAM reproducibility crisis if formal validation were to be abandoned.³

SCFs, such as the one recently adopted by the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods,⁴ provide a scientifically robust and flexible approach to modernize traditional validation. In theory, SCFs can be used by anyone to develop scientific confidence in a NAM for any intended purpose (e.g., product development, regulatory use, etc.). SCFs share common elements of context, biological relevance, technical characterization, transparent data and analysis (e.g., data integrity), and peer review.^4,5 These common elements across these SCFs indicate scientific consensus on the necessary elements of an SCF. Importantly, SCFs do not preclude the ability to conduct extensive ring trials in situations where that may still be desired. It is a shared responsibility of the regulatory science community to press ahead with implementing SCFs for evaluating NAMs to ensure that fit-for-purpose validation achieves the scientific benchmarks needed for acceptance of each NAM for its specific decision context.

Building Scientific and Public Trust in NAMs

The public relies upon scientists to provide reliable and accurate data. The public, and the U.S. Congress for example, would like to see scientists adopt NAMs. However, public and congressional support for NAMs will quickly erode if NAMs are used inappropriately. The discussion of the reliability of data from NAMs and the conclusions drawn therefrom illustrate key principles.⁶⁻⁸ First, regulatory decisions using NAMs must meet rigorous data standards and comply with the context for which specific NAM assays or inference models based on NAMs have been validated. Second, NAMs can be used to generate hypotheses, but such hypotheses must be rigorously tested before being incorporated into regulatory decisions. It is a shared responsibility across the whole of the regulatory science community to ensure NAMs meet these core scientific principles.

Remarks for Future Prospects

Significant advancements over the past several decades have been made in some areas toward the development and adoption of NAMs in the regulatory context. NAMs have the potential to improve the accuracy and relevance of toxicity testing by providing human and environmentally relevant data while reducing reliance on animal testing. Although there has been progress in the development and adoption of NAMs to inform chemical safety assessments, there is a need to continue to adapt and provide flexibility in regulatory frameworks to incorporate NAMs and establish clear guidance for their use.

The authors declare the following competing financial interest(s): S.L.L., L.S.R., and L.L. are employees of Bayer Crop Science, a developer and manufacturer of pest control products, and the information expressed in this article is that of the Bayer authors and does not necessarily represent the view of Bayer Crop Science. R.A.B. and J.P.R. are employed by the American Chemistry Council (ACC, https://www.americanchemistry.com/), an industry trade association that represents a diverse set of companies engaged in the business of chemistry; for a list of ACC members, see https://www.americanchemistry.com/about-acc/membership. The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views or policies of ACC. The information in this paper reflects the views of co-author A.C.B. and does not necessarily reflect the official positions or policies of NOAA or the Department of Commerce. N.B. and L.D.B. have no conflicts to declare and received no funding for this work.