Consensus Report on the Future of Animal-Free Systemic Toxicity Testing

Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council’s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible adaptation to exposure scenarios and individual risk factors

Consensus Report on the Future of Animal-Free Systemic Toxicity Testing

Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council’s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible adaptation to exposure scenarios and individual risk factors

Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients

Consumer safety is a prerequisite for any cosmetic product. Worldwide, there is an ever-increasing desire to bring safe products to market without animal testing, which requires a new approach to consumer safety. ‘Next Generation Risk Assessment’ (NGRA), defined as an exposure-led, hypothesis driven risk assessment approach that integrates in silico, in chemico and in vitro approaches, provides such an opportunity. The bespoke nature of each NGRA means that the development of a prescriptive list of tests to assure safety is not possible, nor appropriate. The International Cooperation on Cosmetics Regulation (ICCR) therefore tasked a group of scientists from regulatory authorities and the Cosmetic Industry to agree on and outline the principles for incorporating these new approaches into risk assessments for cosmetic ingredients. This ICCR group determined the overall goals of NGRA (to be human-relevant, exposure-led, hypothesis-driven and designed to prevent harm); how an NGRA should be conducted (using a tiered and iterative approach, following an appropriate literature search and evaluation of the available data, and using robust and relevant methods and strategies); and how the assessment should be documented (transparent and explicit about the logic of the approach and sources of uncertainty). Those working on the risk assessment of cosmetics have a unique opportunity to lead progress in the application of novel approaches, and cosmetic risk assessors are encouraged to consider these key principles when conducting or evaluating such assessments.JRC.F.3-Chemicals Safety and Alternative Method

Finding Synergies for 3Rs – Toxicokinetics and Read-Across: Report from an EPAA Partners’ Forum

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners’ Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. An important hurdle to PBK modelling is a lack of toxicokinetic data. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetic parameters required for read-across; case studies exemplifying how toxicokinetics data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools; and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to create a database of toxicokinetic tools that assist risk assessment.JRC.F.3-Chemicals Safety and Alternative Method

Finding Synergies for 3Rs – Toxicokinetics and Read-Across: Report from an EPAA Partners’ Forum

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners’ Forum Toxicokinetics and Read-Across to provide an overview on research activities to develop in vitro toxicokinetics methods and physiologically-based kinetic (PBK) models and to find synergies to enhance use of toxicokinetic data to strengthen read-across. In certain sectors, PBK modelling is being used for risk assessment, but less so in others. An important hurdle to PBK modelling is a lack of toxicokinetic data. Preferably, toxicokinetic data should be generated using in vitro and in silico tools and anchored towards human relevance. Specific activities were identified to facilitate the use of in vitro and in silico toxicokinetic data to support read-across: The collation of available tools indicating the parameters and applicability domains covered; endpoint-specific guidance on toxicokinetic parameters required for read-across; case studies exemplifying how toxicokinetics data help support read-across. Activities to enhance the scientific robustness of read-across include the further user-friendly combination of read-across tools; and formal guidance by the authorities specifying the minimum information requirements to justify read-across for a given toxicity endpoint. The EPAA was invited to continue dissemination activities and to explore possibilities to create a database of toxicokinetic tools that assist risk assessment.JRC.F.3-Chemicals Safety and Alternative Method