Chinese translation of the “Guidance Document on the validation and international acceptance of new or updated test methods for hazard assessment”

OECD Series on Testing and Assessment（2005），No.34.

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The genesis of this guidance on the validation and acceptance of test methods was an OECD workshop on the“ Harmonization of validation and acceptance criteria for alternative toxicological test methods”，held in January 1996 in Solna，Sweden.The sets of definitions，principles and criteria emanating from the workshop gained rapid and widespread acceptance since they provided the basis for a coherent and scientifically sound framework that was understandable and workable by all key actors，including test developers，regulators and industrial end-users.In 1998，the OECD commenced the development of this Guidance Document with the aim of ensuring that the decisions and recommendations from the Solna workshop would be eventually translated into standard international practice，not only accelerating the validation and acceptance of new methods worldwide，but also to facilitate international cooperation in the validation process and to expedite the development and acceptance of OECD Test Guidelines.The Guidance Document took seven years to complete，during which more workshops were organised and many commenting rounds undertaken to share a wide variety of expert viewpoints and to collectively deal with the‘devil in the detail’.Eventually in 2005，‘GD34’was adopted and declassified by the OECD and published as part of its Series on Testing and Assessment.So in 2015，the Guidance Document celebrates its 10th birthday，and we can be reassured that its purpose and content remain as valid as ever and are readily applicable to emerging 21st century toxicological testing methods and tools.

In a regulatory content，validation can be viewed as a highly desirable，if not essential step towards the development of test guidelines.Test guidelines based on validated methods provide dependable data that serve to satisfy information requirements linked to the safety assessment and regulatory control of chemicals used in a variety of sectors.Since the testing of chemicals is typically expensive and time consuming，it is desirable for both economic and ethical（animal）reasons that test data generated for a chemical in one region or jurisdiction can be readily used in another.The OECD Council therefore adopted a Council Decision in 1981 on the Mutual Acceptance of Data（MAD），which basically states that in the context of chemical assessment for the protection of human health and the environment，test data generated in any member country in accordance with OECD Test Guidelines and Principles of Good Laboratory Practice（GLP）shall be accepted in other member countries.It is estimated that MAD accounts for total annual savings of approximately 150 Million Euro and tens of thousands of animal lives.Moreover，harmonised approaches to chemical hazard assessment based on internationally accepted test guidelines is an important element in facilitating growth in the global sale of chemicals，now valued at over 3 Trillion Euro per annum.Thus embracing the principles and practice of method validation as described in this Guidance Document not only supports effective and efficient chemical hazard assessment but also contributes considerably to economic growth and job creation.

As defined herein，Validation is stated as the process by which the reliability and relevance of a particular approach，method，process or assessment is established for a defined purpose.Reliability is defined as measures of the extent that a test method can be performed reproducibly within and between laboratories over time，when performed using the same protocol.Although essentially a technical task，establishing the reliability of a method protocol is a challenging endeavour and often accounts for the majority of time and effort invested in a validation study.In order to increase Europe’s capacity to conduct validation ring trials，the European Union Reference Laboratory for Alternatives to Animal Testing（EURL ECVAM）established in 2013 the EU Network of Laboratories for the Validation of Alternative Methods（EU-NETVAL）which comprises 26 highly qualified laboratories with particular expertise on in vitro methods，most of which operate under GLP.However regardless of the competence of the validation laboratories engaged in a study，probably one of the most important factors for a successful ring trial is to start with a method protocol that has been fully optimised，defined，and sufficiently described.This is easier said than done，particularly with modern toxicological methods that increasingly incorporate sophisticated biological test systems（e.g.derived from stem cells or engineered tissue）and high-content measurements（e.g.digital imaging and ‘omics）.

This Guidance defines the Relevance of a method to be the description of the relationship of the test to the effect of interest and whether it is meaningful and useful for a particular purpose.It is the extent to which the test correctly measures or predicts the biological effect of interest.Establishing the relevance of new in vitro methods with respect to（eco）toxicological effects of regulatory concern has become increasingly challenging.This is due to the fact that prediction of more complex toxicological effects typically relies on the optimal combination of results from multiple complementary methods，for example within an Integrated Approach to Testing and Assessment（IATA）.As proposed by the OECD's Task Force on Hazard Assessment，the design of an IATA and the selection of appropriate tests should be guided if possible by mechanistic understanding of the toxicological processes underpinning the apical effect of concern，described ideally as Adverse Outcome Pathways（AOP）.Thus going forward，the relevance of a test method can be validated in terms of its ability to capture one or more 'key events' of an AOP，rather than its potential to predict an apical in vivo effect in a standalone manner.Ultimately then，the overall utility and level of regulatory acceptance of a validated method will depend on the value of information it provides as a component within IATA addressing different aspects of hazard identification，characterisation or quantitative safety assessment.

As ever，the primary purpose of validation is to provide an essential step towards regulatory acceptance of a test method.Moreover，the eight validation principles describe in this Guidance Document have clearly stood the test of time.What has changed continually however is the process which we adopt to undertake a validation study.The 'modular approach' to validation was introduced by EURL ECVAM over a decade ago and laid the conceptual foundation to decouple independent elements of the validation process to introduce more flexibility and efficiency.For example，by separating the assessment of inter-laboratory reproducibility from the evaluation of predictive capacity it is possible to assess the latter first within a single laboratory，before embarking on a potentially technically and logistically challenging ring trial.At EURL ECVAM this approach allows us to employ robotic High Throughput Screening platforms to make an early judgement on the relevance of an assay before we assess its overall reliability.Another innovation in the validation arena is the concept of validating for the purpose of defining performance standards for a particular class of method，rather than validating a single method.This reflects the fact that different methods having a similar technical basis（e.g.in vitro gene-reporter assays using different cell lines but addressing the same toxicological mechanism or pathway）can produce essentially the same information.Methods that comply with the same performance standards（inc.specified reference chemicals）can be then included in an OECD Performance Based Test Guideline（PBTG）which provides a user with an option to generate information for regulatory purposes using their method of choice.Moreover，the validation of other similar or'me too'methods is then a more straightforward task since the scope is restricted to demonstrating compliance with the established standards.

In November 2013，I had the honour to be invited to speak at the 6th National Congress of Toxicology of the Chinese Society of Toxicology（CSOT-VI），held in Guangzhou，Guangdong Province.Not only was it my first time at CSOT，but also my first time in China.I found the experience extremely rewarding，both personally and professionally.In particular，the enthusiasm，commitment and intelligence of the many young scientists present gave the sense that anything is possible once the goal is identified.That goal should be the realisation of an internationally harmonised hazard assessment framework that exploits the latest advancements in science，provides the highest levels of protection for human health and the environment，avoids animal testing，relies upon OECD Test Guidelines，is applicable across all sectors and jurisdictions，and ensures MAD.China can play a pivotal role in the realisation of this 'new paradigm'，building on the current state-of-the-art through coordinated initiatives and investment that capitalises on its considerable resources and expert scientific community.Participation at the OECD and in bodies such as the International Cooperation on Alternative Testing Methods（ICATM）will ensure that China pushes confidently forward in this field in cooperation with global partners.

European Union Reference Laboratory for Alternatives to Animal Testing

（EURL ECVAM）,

Institute for Health and Consumer Protection,

European Commission Joint Research Centre,

Ispra,Italy.