Scientific Usefulness of New Approach Methodologies

New approach methodologies (NAMs) are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment, and avoid the use of animals, and may include in silico, in chemico, in vitro, and ex vivo approaches.^1,2

The usefulness of NAMs is gaining recognition as a number of roadmaps are being published to help advance the acceptance and use of NAMs at the regulatory level.^2–7 Today, it is possible to replace animal testing for assessing certain toxicological endpoints such as skin irritation and corrosion, ocular hazard assessment, and skin sensitization (OECD, GD 203; OECD GD TG 491B; OECD GL 497). Such replacements often require the use of integrated approaches in the form of Integrated Approaches to Testing and Assessment Defined Approaches to Testing and Assessment, and/or making use of mechanistic knowledge gained through analytical constructs, for example, Adverse Outcome Pathways (AOPs). ⁸ For instance, today more than 450 AOPs have been submitted to the AOP wiki platform (www.aopwiki.org).

The use of NAMs within integrated strategies, combined with the knowledge of the underlying biological process, can contribute to a more mechanistic and predictive human science while decreasing the animal studies that may be necessary. Advanced human-based NAMs have the potential to improve preclinical testing, as studies relying on animals to characterize effects of chemicals can be of questionable or limited biological relevance to human effects.^9–12 In the pharmaceutical area, a recent study reports that alternatives to animal testing could also reduce the approval time for the entry into market of the new COVID-19 vaccines. ¹³ Furthermore, the pathogenesis of COVID-19 has been modeled using the AOP framework and networks to better understand the disease. ¹⁴

There is broad support for developing robust and efficient processes to gain scientific confidence in NAMs and accelerate their implementation at the regulatory level. A new framework for establishing scientific confidence in NAMs has been recently proposed, based on five essential elements: fitness for purpose, human biological relevance, technical characterization, data integrity and transparency, and independent review. ¹⁵

The use of Good In Vitro Method Practices (GIVIMP) has also been proposed to help improve the scientific integrity (relevance), quality (reproducibility), and reduce the uncertainties of predictions based on in vitro methods used for scientific purposes (OECD, GD 286). A new certification program has also been proposed to further increase confidence in in vitro methods. ¹⁶

An e-learning module is available at the Education and Training Platform for Laboratory Animal Sciences (ETPLAS), which provides guidance to method developers and other parties interested in improving the speed and efficiency with which new in vitro methods and approaches are developed, tested, optimized, and implemented for scientific and regulatory uses.*

The present AIVT issue provides with three good examples of how NAMs and their integration can be applied to a variety of purposes. The first article (pgs. 67–82) represents a joint effort from industry, regulators, and an intergovernmental organization, and reports on the standardization and optimization of a NAM according to GIVIMP. In this way, the reproducibility of the method was demonstrated, and a set of acceptance criteria defined to assess the validity of assay runs. In addition, strategies were implemented to verify the specificity of DIO1 interaction to study thyroid hormone disturbance.

In the second article (pgs. 83–101), a set of 18 in vitro studies were used, and their predictiveness to identify the local acute irritation of two fungicides was reported. Discussions in particular addressed the potential impact of species differences in the obtained results. Finally, in the third article (pgs. 102–112) an integrated in vitro approach was used to assess the potential for skin and eye irritation, alteration of neuronal activity, and the environmental toxicity of natural algal toxins. As a whole these articles demonstrate the applicability of NAMs for identifying important toxicological data and improving the regulatory process.