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New Approach Methodology (NAM)

New Approach methodology (NAM) is an overarching term and as described by the Organisation for Economic Co-operation and Development (OECD) can include in vitro (e.g. omics, cell-based, tissue-based, etc.) assays, in silico (e.g. [Q]SARs, expert systems, etc.) models, and other biotechnological and computational approaches such as physiologically based kinetic (PBK) models. NAMs can serve as (replacement, reduction or refinement) alternatives to animal testing.

NAMs may play a crucial role in safety assessment of agrochemicals as they have the potential to provide an efficient, biologically relevant and cost-effective way to assess the potential toxicity of chemical compounds without the need for animal testing. NAMs are key components of Integrated Approaches to Testing and Assessments (IATAs), described by the Organisation for Economic Co-operation and Development (OECD) in 2020. IATAs represent a flexible framework for carrying out an assessment and reaching a regulatory conclusion with the purpose of evaluating risk to human health and the environment from chemical exposure.

Many NAMs have been developed and been subject to international validation procedures via the OECD. Many regulators are also looking to increase the use of NAMs to phase out and replace mandatory vertebrate testing, and several research and regulatory groups are actively proposing strategies to facilitate this. In the United States of America, the Environmental Protection Agency (US EPA) and Food and Drug Administration (US FDA) intend to reduce animal testing, and in Europe, the European Food Safety Authority (EFSA), European Chemicals Agency (EChA) and European Medicines Agency (EMA) are also developing strategies to include NAMs in regulatory safety assessments.

Data requirements on the mandated use of NAMs vary by region and endpoint. This raises the practical question of what to use when there is uncertainty about regulatory acceptance of the data. NAMs have been frequently used in the assessment of human relevance, such as hepatocellular proliferation in vitro and effects on the thyroid axis however, with variable regulatory impact and acceptance.

The CropLife Europe ‘in vitro in vivo extrapolation’ (IVIVE) subgroup has defined key focus areas related to NAMs including addressing recurring issues occurring in in vitro assays used for safety assessment, contributing to the review of guidelines and draft guidelines, and reviewing appropriate techniques for exposure assessment utilizing NAMs.

CropLife Europe IVIVE subgroup contributions:

1. The influence of cell culture practice and cytotoxicity: To achieve regulatory endorsement of NAMs, it is critical that they are robust and reliable. Both cell culture practice and cytotoxicity can confound the study outcomes, and its influence is often not well understood in early stages before full validation and experience exist. The IVIVE subgroup is reviewing critical steps of cell culture practice methodologies to assess cytotoxicity and its potential influence on assay outcomes. Key findings are planned to be made available with a peer reviewed paper.

2. Exposure modelling tools: The CLE IVIVE subgroup conducted a survey to understand which pharmacokinetic modelling tools are used by industry and how they are utilized to predict in vivo exposure. Output of this survey highlighted frequently used models for predicting dose and exposure relationships in key species as well as common ways of working in the application of these types of models within risk assessment scenarios. The group are currently evaluating the three generic/open-source models (HTTK, PK-Sim and TKplate) identified as commonly used by all CLE participating companies or emerging model. The models will be bench-marked for their predictivity of systemic exposure for a range of plant protection products. Key findings will be made available with a peer reviewed paper.

For information regarding these software products, see:

HTTK: Pearce RG, Setzer W, Strope CL, Wambaugh and Sipes NS, 2017. httk: R Package for High-Throughput Toxicokinetics. Journal of Statistical Software. 79(4):1-26. doi: 10.18637/jss.v079.i04

TKplate: Bossier B, Cortiñas-Abrahantes J, Darney K, Spyropoulos F, Lautz LS, Billat PA, RémyBeaudouinR,Zeman F, Bodin C,Dorne, JLCM.2023. User Guide for TKPlate 1.0. An open access platform for implementing new approach methodologies in chemical risk assessment through toxicokinetic and toxicodynamic modelling. EFSA supporting publication 2023:20 (11): EN-8441. 46pp.doi:10.2903/sp.efsa.2023.EN-8441