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Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The toxicological assessment of chemically complex food matrices (CCFM) usually is very time consuming, expensive and uses many animal studies. Improvements to obtain a more efficient assessment process remain limited as long as we retain traditional approaches to toxicological risk assessment. New concepts would be needed to achieve real innovations in risk assessment. The threshold of toxicological concern (TTC) potentially is such a concept that has existed for many years and recently has been further developed. The safety of CCFM is difficult to assess as there are numerous unknown substances present (often referred to as 'Forest-of-Peaks' in chromatographic analysis). Usually, for the evaluation of CCFM, a full safety assessment approach involving animal studies is needed, but the exposure to most substances is low and TTC might be applicable. However, to apply TTC efficiently to CCFM, a strategy is needed to deal with large numbers of unknowns (substances of which structural information is lacking). Therefore, we have drafted a framework for application of TTC in safety assessment of CCFM. This paper describes the criteria and development of the framework proposing a stepwise approach for the application of TTC in safety assessment of CCFM and future developments required., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Implementation of reliable methodologies allowing Reduction, Refinement, and Replacement (3Rs) of animal testing is a process that takes several decades and is still not complete. Reliable methods are essential for regulatory hazard assessment of chemicals where differences in test protocol can influence the test outcomes and thus affect the confidence in the predictive value of the organisms used as an alternative for mammals. Although test guidelines are common for mammalian studies, they are scarce for non-vertebrate organisms that would allow for the 3Rs of animal testing. Here, we present a set of 30 reporting criteria as the basis for such a guideline for Developmental and Reproductive Toxicology (DART) testing in the nematode Caenorhabditis elegans. Small organisms like C. elegans are upcoming in new approach methodologies for hazard assessment; thus, reliable and robust test protocols are urgently needed. A literature assessment of the fulfilment of the reporting criteria demonstrates that although studies describe methodological details, essential information such as compound purity and lot/batch number or type of container is often not reported. The formulated set of reporting criteria for C. elegans testing can be used by (i) researchers to describe essential experimental details (ii) data scientists that aggregate information to assess data quality and include data in aggregated databases (iii) regulators to assess study data for inclusion in regulatory hazard assessment of chemicals. [ABSTRACT FROM AUTHOR]

Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study. [ABSTRACT FROM AUTHOR]

Toxicology and safety assessment are changing and require new strategies for evaluating risk that are less depending on apical toxicity endpoints in animal models and relying more on knowledge of the mechanism of toxicity. This manuscript describes a number of developments that could contribute to this change and implement this in a stepwise roadmap that can be applied for the evaluation of food and food ingredients. The roadmap was evaluated in four case studies by using literature and existing data. This preliminary evaluation was shown to be useful. However, this experience should be extended by including examples where experimental work needs to be included. To further implement these new insights in toxicology and safety assessment for the area of food and food ingredients, the recommendation is that stakeholders take action in addressing gaps in our knowledge, e.g. with regard to the applicability of the roadmap for mixtures and food matrices. Further development of the threshold of toxicological concern is needed, as well as cooperation with other sectors where similar schemes are under development. Moreover, a more comprehensive evaluation of the roadmap, also including the identification of the need for in vitro experimental work is recommended. [ABSTRACT FROM AUTHOR]

Abstract: At the IVTIP (In Vitro Testing Industrial Platform) meeting of November 26th 2009 entitled ‘Toxicology in the 21st century (‘21C’) – working our way towards a visionary reality’ all delegates endorsed the emerging concept of the ‘21C’ vision as the way forward to enable a thorough, reliable and systematic approach to future toxicity testing without the use of animals. One of the emerging concepts focused on integrating a defined number of tests modelling in vivo-relevant and well-characterised toxicity pathways representing mechanistic endpoints. At this meeting the importance of Integrated Testing Strategies (ITS) as tools towards reduction and eventually replacement of the animals currently used for hazard identification and risk assessment was recognised. A follow-up IVTIP Spring 2010 meeting entitled ‘Integrated In Vitro Testing Strategies (ITS) – Implementation Challenges’ was organised to address pending questions about ITS. This report is not a review of the ITS literature, but a summary of the discussions triggered by presented examples on how to develop and implement ITS. Contrasts between pharmaceutical and chemical industry, as well as a list of general but practical aspects to be considered while developing an ITS emerged from the discussions. In addition, current recommendations on the validation of ITS were discussed. In conclusion, the outcome of this workshop improved the understanding of the participants of some important factors that may impact the design of an ITS in function of its purpose (e.g. screening, or early decision making versus regulatory), the context in which they need to be applied (e.g. ICH guidelines, REACH) and the status and quality of the available tools. A set of recommendations of best practices was established and the importance of the applicability of the individual tests as well as the testing strategy itself was highlighted. [Copyright &y& Elsevier]

Abstract: A workshop to reappraise the previous IWGT recommendations for photogenotoxicity testing [E. Gocke, L. Muller, P.J. Guzzie, S. Brendler-Schwaab, S. Bulera, C.F. Chignell, L.M. Henderson, A. Jacobs, H. Murli, R.D. Snyder, N. Tanaka, Considerations on photochemical genotoxicity: report of the International Workshop on Genotoxicity Test Procedures working group, Environ. Mol. Mutagen., 35 (2000) 173–184] was recently held as part of the 5th International Workshop on Genotoxicity Testing (IWGT) meeting in Basel, Switzerland (August 17–19, 2009). An Expert Panel was convened from regulatory, academic and industrial scientists (with several members serving on the original panel) and chaired by Dr Peter Kasper (BfArM, Germany). The aim of the workshop was to review progress made in photo(geno)toxicity testing over the past decade; a period which saw the introduction of several regulatory photosafety guidances in particular in Europe and the USA. Based on current regulatory guidelines a substantial proportion of compounds trigger the requirements for photosafety testing. Moreover, there has been growing concern within industry about the performance of the in vitro photosafety tests in the “real world” of compound development. Therefore, the expert group reviewed the status of the current regulatory guidance''s and the impact these have had on compound development in the context of the various triggers for photosafety testing. In addition, the performance of photogenotoxicity assays (old and new) was discussed, particularly in view of reports of pseudophotoclastogencity. The Expert Panel finished with an assessment of the positioning of photogenotoxicity testing within a photosafety testing strategy. The most significant conclusion made by the Expert Panel was that photogenotoxicity testing should no longer be recommended as part of the standard photosafety testing strategy. In addition, progress was made on the refinement of triggers for photosafety testing. For example, there was support for harmonisation of methods to determine the Molar Extinction Coefficient (MEC) and a consensus agreement that there should be no requirement for testing of compounds with a MEC<1000Lmol−1 cm−1. [Copyright &y& Elsevier]