New Approach Methodologies (NAMs)

New Approach Methodologies

In recent years, there has been interest in developing new, faster and less expensive approaches to collect toxicological information. These methods, which researchers aspire to develop for use in place of traditional animal testing, are referred to as new approach methodologies (NAMs). NAMs are defined as any technology, methodology, approach, or combination that can provide information on chemical hazard and risk assessment without the use of animals, including in silico, in chemico, in vitro, and ex vivo approaches (ECHA, 2016b; EPA, 2018d). Several roadmaps have been developed recently (e.g., US EPA, EFSA) to support the implementation of NAMs and aiming towards a full replacement of animal testing.

Regulatory agencies worldwide have recognized the importance of the timely uptake of fit for purpose NAMs for hazard and risk assessment and are introducing flexible, efficient, and scientifically sound processes to establish confidence in the use of NAMs for regulatory decision-making (van der Zalm et al., 2022; Ingenbleek et al., 2020).

The EU Regulatory context and challenges for non-animal approaches

The primary objective of EU legislation regulating industrial chemicals is to ensure a high level of protection of human health and the environment while promoting the use of alternative methods and maintaining competitiveness of the EU chemical sector. REACH and CLP are the two European regulations that have the aim of protecting the health of the population (workers, consumers) and the environment in the correct use of chemical substances. The current regulatory system achieves this purpose making use of animal testing as a last resort. Therefore, it can be maintained as a framework for transitioning to an animal-free regulatory system. Some shortcomings in the current regulatory system have been identified in the Chemicals Strategy for Sustainability (CSS), setting the direction for the imminent revision of this system. The CSS also clearly lays down the expectation to move towards a reduced reliance on animal testing.

NAMs have been developed and used in hazard and risk assessment so far at three different levels within the REACH and CLP context:

  • – by registrants in support of hazard identification and classification,
  • – by registrants to support read-across and category approaches,
  • – by authorities to support screening and priority setting by identifying potential substances of concern for further data gathering and assessment including when the concerns need to be further addressed by animal testing.

The needs or expectations for NAMs are different depending on legislation (sectoral or horizontal), type of chemistry and depending on what the data are used for. There are currently only a few endpoints where full replacement of in vivo studies with non-animal methods has been accepted in a way that is suitable for classification and labelling or to conclude on (no) hazard: skin sensitisation, skin and eye irritation and (partially) genotoxicity. For other more complex toxicological endpoints, such as repeated dose toxicity, reproductive toxicity, carcinogenicity and long term aquatic toxicity or bioaccumulation, the mandatory information requirements still rely on animal testing, although several initiatives are actively exploring opportunities to fulfil standard information requirements through a combination of approaches, including the use of cell transformation assays (CTAs), QSARs, toxicokinetics, and other in vitro assays and computational tools.

Full replacement of animal testing still requires advancement in the scientific developments.

Identification of the critical elements necessary to transit to a non-animal system

To facilitate a smooth and responsible transition, the first step is to identify what are the critical elements needed to enable hazard and risk assessment without reliance on animal testing. In principle, a new, animal-free system will need to allow conclusions whether a substance does or does not have hazardous properties. In addition, in case that a toxic property has been identified, also the level of its severity should be determined (effect type and its potency).

Therefore, the critical needs to be addressed are, at the minimum:

  • NAMs for hazard identification: The ability to demonstrate that NAMs, (e.g., an integrated in vitro/in silico system) can be used to allow a conclusive outcome on the (lack of) hazardous properties for given regulatory endpoint; the conclusion that the substance does not have a certain hazardous property should be sound;
  • NAMs for hazard characterisation: The ability to reliably identify hazard and derive reference values based on changes at the molecular/cellular level instead of observed adversity in an organism. And to inform how severe the toxic effect is for human health or environment;
  • NAMs for extrapolation: The ability to reliably convert nominal concentrations measured or predicted by NAMs (e.g., concentration in a tissue culture medium) into external doses used to set safety levels (e.g., mg/kg bodyweight), to communicate the hazard and assess the risks.

In addition to the three critical elements described above, the combination of various NAMs will be needed to cover more complex endpoints. Consequently, in addition to the test methods and/or predictive models also the explicit rules for the evidence integration and derivation of the overall outcome also needs to be developed and implemented.

OECD plays a strategic role in harmonizing approaches and gaining wider acceptance for NAMs. Ensuring the internationally harmonized application of the NAM methodologies as well as mutual acceptance of NAM data between jurisdictions will be key to bring such methodologies into general use. It is therefore expected that the OECD programmes will evolve in line with the developments of NAMs, including finding appropriate ways of validating their relevance and reliability to increase the confidence of regulators and users in the results from such tests.

Conclusions

Replacing animal testing with industrial chemicals, while ensuring a high level of protection, is an objective shared by all stakeholders at EU level. Global alignment is also a critical success factor, based on the alignment of the CLP criteria with the Globally Harmonized System (GHS). Pursuing this ambition requires close and effective cooperation between stakeholders, through open dialogues and concerted actions. All stakeholders will need to do their part to ensure progress in research, standardization/validation and implementation of methods. Exchange with external stakeholders provides different perspectives and experiences with different NAMs.

ECHA is fully committed to doing its part to support policy makers in developing an adequate and coherent approach to the regulation of chemicals based on the increased use of NAMs and, ultimately, the phasing out of animal testing.

It is important to provide ongoing education opportunities to regulators and stakeholders on the conditions under which the application of a given NAM is appropriate and how data from that NAM is interpreted. Conferences and webinars are examples of such opportunities. Another key factor in advancing NAMs is the opportunity to discuss proposed NAM testing strategies with the agency.

Furthermore, national and international communication and collaboration within and across sectors and geographies are of the utmost importance to minimize duplicative efforts and efficiently advance the best science. Ultimately, regulatory frameworks that allow for the timely adoption of scientifically valid approaches to toxicology testing will facilitate the global acceptance of NAMs and enable the best protection of human health.

At ToxHub, we advocate for the 3R principles, and we do our best to avoid the use of animal testing, prioritizing alternative methods whenever feasible for our clients.

 

 

Article issued by Maria Labianca

 

Bibliography

https://echa.europa.eu/documents/10162/21184118/2023_06_01_nam_workshop_background_note_en.pdf/18873078-7ef6-80d3-b929-3b5a782949c9?t=1684306840053

https://echa.europa.eu/documents/10162/23919267/230530_117_3_alternatives_test_animals_2023_en.pdf/9cfc291e-9baf-ffa2-466c-2bc2c6f06b8e?t=1685428213290

ECHA (2016b). New approach methodologies in regulatory science. Proceedings of a scientific workshop. Helsinki: European Chemicals Agency. doi:10.2823/543644

EPA (2018d). Strategic plan to promote the development and implementation of alternative test methods within the TSCA program. U.S. Environmental protection agency. EPA-740-R1-8004. Available at: https://www.epa.gov/sites/default/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf.