A new regulatory paradigm for increased robustness in chemical testing

Traditional animal-based methods for testing chemicals are costly, time-consuming and come with an ethical burden. Though they have been essential for chemical testing, their status as the ‘gold standard’ is waning in some areas as new technologies emerge. Governments and industry worldwide are now enthusiastic about ‘new approach methodologies’ (NAMs) – non-animal methods that are becoming more accurate, reliable, quick and cost-effective for assessing the toxicity of chemicals. 

Most NAMs do not seek to provide a like-for-like replacement or simulation of an existing animal test, but instead approach the problem from a data-driven and mechanistic perspective that provides a deeper biological understanding of the toxic mechanisms involved. This allows for more human-relevant and species-specific assessments that meet or exceed the standards of animal tests. Examples include: in silico approaches – computer modelling or simulations, such as quantitative structure-activity relationships (QSARs), which predict how chemicals interact with biological components based on the chemical’s structure; in vitro methods, that test effects of chemicals outside a living organism using, for example, organ-specific cell lines or tissues; in chemico methods, measuring reactivity of chemicals with biological molecules; and omics methods that measure exposure-driven changes in the abundance of gene products and metabolites.

NAMS could also allow improved data sharing between different areas of chemical assessment, from medicines and foods to industrial chemicals. This could reduce the costs of assessing safety and encourage innovation while providing more accurate and reliable information, benefiting businesses and regulators.

Significant work has been put into developing new approaches that can improve decision-making in chemical safety assessment, such as grouping substances for read-across. This is a technique for predicting toxicity information for one substance or species by using data for other substances or species that share some of their characteristics. NAMs can also help to assess chemicals for which little toxicity data exist, for example, by grouping substances along with data-rich chemicals using omics and other available mechanistic data. This can support hypotheses that chemicals share toxicity pathways, or can fill data gaps, providing higher confidence in risk assessments.

By establishing international standards, we can expedite global acceptance

The development of shared tools and standards for NAMs are taking centre stage at international organisations such as the Organisation for Economic Co-operation and Development (OECD), where guidance for NAMs-based tests is being developed for increasingly complex pathways, such as endocrine disruption and neurotoxicity. Currently, single stand-alone NAMs are already used and under development for regulatory purposes, including for the assessment of relatively simple endpoints, and for grouping, screening or prioritisation in a tiered safety assessment – a hierarchy of tests that starts with existing information and simple methods, such as biochemical or cell-based assays, before proceeding to more complex methods usually involving live animals. In the longer term, combinations of different NAMs will enable us to assess toxicity involving more complex chemical and biological pathways with greater certainty. This is illustrated by the recently adopted Guideline on Defined Approaches for Skin Sensitisation from the OECD, which is the first test guideline to completely replace an animal test. These Defined Approaches use specific combinations of in silico, in chemico and in vitro tools, with fixed Data Interpretation Procedures, to overcome the limitations and uncertainty of individual methods. These combined techniques can help to produce equally or more informative and reliable data than traditional animal assays. This milestone was achieved through substantial cooperation between OECD countries, including the UK, and will pave the way for similar advancements. By establishing international standards and guidance for regulatory use of NAMs and reporting of data, we can expedite global acceptance.

To support these data-driven approaches, efforts are being invested across governments, academia and industry into framing our mechanistic understanding of molecular pathways activated or disturbed by chemicals into Adverse Outcome Pathways (AOPs), which map how early molecular events ultimately lead to toxic outcomes. NAMs can then be designed to target key molecular events identified in these AOPs. By providing information on the pathways of toxicity, NAMs can inform on which chemicals are toxic and why.

There is a vast amount of work being done domestically and internationally to advance NAMs. For example, a NAMs roadmap is being developed by the Food Standards Agency and the Committee on Toxicity, and, as well as work in the OECD, the UK collaborates on numerous international research consortia, such as PrecisionTox.

NAMs have the potential to deliver more efficient, reliable and relevant chemical safety testing tools. Through this, NAMs may bring a new regulatory paradigm that better protects both humans and the environment while reducing animal testing.

Acknowledgement

We would like to thank John Colbourne for reviewing the article