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Acceptance criteria for new approach methods in toxicology and human health-relevant life science research – part I

Feb 8, 2024 | 2023, Altex, Journal publications

Abstract

Every test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects, and mistakes introduced by operators, laboratory equipment, or materials used. Adherence to an SOP and comprehensive validation of the test method cannot guarantee that each test run produces data within the acceptable range of variability and with the precision and accuracy determined during the method validation. We illustrate here (part I) why controlling the validity of each test run is an important element of experimental design. The definition and application of acceptance criteria (AC) for the validity of test runs is important for the setup and use of test methods, particularly for the use of new approach methods (NAM) in toxicity testing. AC can be used for decision rules on how to handle data, e.g., to accept the data for further use (AC fulfilled) or to reject the data (AC not fulfilled). The adherence to AC has important requirements and consequences that may seem surprising at first sight: (i) AC depend on a test method’s objectives, e.g., on the types/concentrations of chemicals tested, the regulatory context, the desired throughput; (ii) AC are applied and documented at each test run, while validation of a method (including the definition of AC) is only performed once; (iii) if AC are altered, then the set of data produced by a method can change. AC, if missing, are the blind spot of quality assurance: Test results may not be reliable and comparable. The establishment and uses of AC will be further detailed in part II of this series.

REACH out-numbered! The future of REACH and animal numbers

Feb 7, 2024 | 2023, Altex, Journal publications

Abstract

The EU’s REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) Regulation requires animal testing only as a last resort. However, our study (Knight et al., 2023) in this issue reveals that approximately 2.9 million animals have been used for REACH testing for reproductive toxicity, developmental toxicity, and repeated-dose toxicity alone as of December 2022. Currently, additional tests requiring about 1.3 million more animals are in the works. As compliance checks continue, more animal tests are anticipated. According to the European Chemicals Agency (ECHA), 75% of read-across methods have been rejected during compliance checks. Here, we estimate that 0.6 to 3.2 million animals have been used for other endpoints, likely at the lower end of this range. The ongoing discussion about the grouping of 4,500 regis-tered petrochemicals can still have a major impact on these numbers. The 2022 amendment of REACH is estimated to add 3.6 to 7.0 million animals. This information comes as the European Parliament is set to consider changes to REACH that could further increase animal testing. Two proposals currently under discussion would likely necessitate new animal testing: extending the requirement for a chemical safety assessment (CSA) to Annex VII substances could add 1.6 to 2.6 million animals, and the registration of polymers adds a challenge comparable to the petrochemical discussion. These findings high-light the importance of understanding the current state of REACH animal testing for the upcoming debate on REACH revisions as an opportunity to focus on reducing animal use.

Guidance document on Good Cell and Tissue Culture Practice 2.0 (GCCP 2.0)

Mar 13, 2023 | 2022, Altex, Journal publications

Abstract

Good Cell and Tissue Culture Practice (GCCP) 2.0 is an updated guidance document from GCCP 1.0 (published by ECVAM in 2005), which was developed for practical use in the laboratory to assure the reproducibility of in vitro (cell-based) work. The update in the guidance was essential as cell models have advanced dramatically to more complex culture systems and need more comprehensive quality management to ensure reproducibility and high-quality scientific data. This document describes six main principles to consider when performing cell culture including characterization and maintenance of essential characteristics, quality management, documentation and reporting, safety, education and training, and ethics. The document does not intend to impose detailed procedures but to describe potential quality issues. It is foreseen that the document will require further updates as the science and technologies evolve over time.

On the usefulness of animals as a model system (part I): Overview of criteria and focus on robustness

Mar 3, 2023 | 2022, Altex, Journal publications

Abstract

Banning or reduction of the use of animals for laboratory experiments is a frequently-discussed societal and scientific issue. Moreover, the usefulness of animals needs to be considered in any decision process on the permission of specific animal studies. This complex issue is often simplified and generalized in the media around the question, “Are animals useful as a model?” To render an often emotional discussion about animal experimentation more rational, it is important to define “usefulness” in a structured and transparent way. To achieve such a goal, many sub-questions need to be asked, and the following aspects require clarification: (i) consistency of animal-derived data (robustness of the model system); (ii) scientific domain investigated (e.g., toxicology vs disease modelling vs therapy); (iii) measurement unit for “benefit” (inte-grating positive and negative aspects); (iv) benchmarking to alternatives; (v) definition of success criteria (how good is good enough); (vi) the procedure to assess benefit and necessity. This series of articles discusses the overall benchmarking process by specifying the six issues. The goal is to provide guidance on what needs to be clarified in scientific and political discussions. This framework should help in the future to structure available information, to identify and fill information gaps, and to arrive at rational decisions in various sub-fields of animal use. In part I of the series, we focus on the robustness of animal models. This describes the capacity of models to produce the same output/response when faced with the “same” input. Follow-up articles will cover the remaining usefulness aspects.

On the Usefulness of Animals as a Model System (Part II): Considering Benefits within Distinct Use Domains

Mar 2, 2023 | 2022, Altex, Journal publications

Abstract

In many countries, animal experiments can only be performed when their necessity has been demonstrated in a legal document. As the usefulness of animals in research is also a significant societal and political issue, criteria to structure debates and evaluations are needed. Here, background information is given on laboratory animal studies. Moreover, parameters that may be considered in judging their usefulness are suggested. The discussion is strictly focused on animals used as tools/test systems/models to provide information on humans. In this context, general features and performance characteristics of models are discussed. Examples are given for well-recognized criteria (e.g., robustness, relevance, predictivity) to judge the usefulness of predictive models. The main hypothesis put forward here is that a benefits evaluation (usefulness metrics) is only possible within sharply circumscribed “use domains”. Examples are given for the research fields of drug and vaccine research, toxicology, disease pathogenesis, and basic biological research. Efficacy, safety, and quality studies are highlighted as “use domains” within the field of drug discovery and production. A further separation into individual diseases, drug targets or symptoms is suggested for, e.g., efficacy studies or pathophysiology. Finally, an outlook is given on the evaluation of model advantages and disadvantages to arrive at their “net benefit”. Moreover, the need to compare the net benefits of animal models versus that of their alternatives is highlighted.