Finding the Right Alternative Model for Regulatory Testing

Regulatory frameworks and alternatives in safety assessment | Sylvia Pelgrom, Charles River, Den Bosch

The 3R principle is included in many legislations, both inside and outside the EU. In general it is stated that the 3R principles are supported and alternative testing needs to be considered before animal tests are performed. And in case of animal testing, reduction and refinement is important to consider. Detailed guidance and regulation, however, is not available, and also the acceptance of alternative data for safety assessment by authorities is not straightforward.

For REACH, some non-animal test strategies are now required and accepted in case of clear results. For other legislations, alternative testing is not legally required, and sometimes even animal tests are included in the legal requirements. The differences in regulatory acceptance results in discussions to come to acceptable testing strategies to fulfill the data requirement for toxicity endpoints.

Pharmacokinetics: Basic principles and examples | Mira Wenker, Charles River, Den Bosch

REACH regulation allows for Read-Across assessment on the basis of (bio)transformation. However, information on (pharmaco-)kinetics and biotransformation is usually lacking for industrial compounds. In addition, regulations do not describe which type of study or what data are necessary. This talk will describe some of the basic principles of pharmacokinetics, what in vitro studies and in vivo studies can be performed and how to use and interpret the data.

In vitro modelling kinetics/metabolism: challenges and possibilities | Arne van Schanke, Certara, Oss

Modeling and simulation plays a key role in drug development from early drug discovery to eventual registration and beyond. Generic applications have been developed to enable prediction of molecular properties, drug absorption, distribution, metabolism and excretion and drug effects. Physiology based pharmacokinetic modeling (PBPK) is a good way to ultilise existing data from both preclinical and clinical research, and to leverage knowledge obtained with one compound to make predictions about other compounds. PBPK is increasingly used in the prediction and optimization of drug absorption and mutual pharmacokinetic interactions between drugs. From a cost perspective, PBPK can help optimizing the timing of costly clinical trials, help in the translation of preclinical to clinical dose selection, selecting key studies to perform and optimizing the design of such studies. Through numerous cycles of “learn-predict-confirm”, the technique has become mature enough to replace part of the clinical studies that were previously required for regulatory approval, reflecting the high confidence that this approach has earned.

Importantly, there are also limitations in the precision of the predictions and in the extrapolations they can support. Such limitations are posed primarily by the assumptions on which the model is based and secondarily, by the quality and type of data used as input for models. A comparison of predicted versus observed data remains a critical quality attribute to assure meaningful results.

Although modeling has gained ground in toxicology, its full potential in prioritizing, optimizing and avoiding studies may yet to be unlocked

Alternative skin sensitisation testing strategy and challenges in practice | Walter Westerink, Charles River, Den Bosch

REACH regulation requires an alternative testing strategy for the assessment of skin sensitization with a focus on non-animals methods. Results obtained with the currently regulatory accepted non-animal methods do not always give a definite conclusion on skin sensitising properties of a chemical. In such cases testing in animals may still be needed. Important challenges with the currently available, validated non-animal methods are the lack of skin metabolism and potency indication and the fact that dermal absorption (due to low solubility or high molecular weight) is not taken into consideration. The current regulatory accepted non-animal methods will be discussed and results of various chemicals including mono-constituents, multi-constituents and UVCBs using the alternative test strategy will be presented.

The Sens-IS assay, a tool to measure the skin sensitization hazard of finished products and the potency of ingredients | Hervé Groux, Immunosearch, Le plan de Grasse, France

The SENS-IS assay, that is at the end of the ECVAM validation process and has been included in the OECD guideline preparation schedule and is the first in vitro assay that can predict skin sensitisation potency of chemical ingredients with a similar accuracy as the animal assay, the LLNA. The assay uses human 3D epidermis as its test system to reflect the real life situation. The read-out uses the robustness and precision of genomic signature measured by multi-target quantitative RT-PCR. The assay has an accuracy as compared to the LLNA or human data of more than 90% not only for hazard assessment but also for the potency classification according to the GHS rules i.e.,Cat 1A or Cat 1B. Because it uses human 3D epidermis the SENS-IS assay can evaluate the hazard of a wide variety of chemicals whatever their solubility, but also mixtures and finished products. Moreover, for finished products the assay can evaluate both irritation and sensitisation hazard.

Identification of Endocrine Disruptors: is it (biologically) plausible? | Majorie van Duursen, Free University, Amsterdam

Endocrine disruption is gaining increasing attention in substance evaluation processes under various regulatory frameworks. While the European Commission has defined criteria to identify and endocrine disrupting chemical (EDC), the practical implementation of EDC identification is challenging. Here, much emphasis is placed on mechanistic understanding on how an EDC can cause an adverse effect, preferably using Adverse Outcome Pathways (AOPs). This presentation will address opportunities and challenges in EDC identification within the regulatory context.

Strategies and tools for evaluating thyroid hormone disruption in vitro | Jeroen Rijk, Charles River, Den Bosch

There is an increased concern that chemicals can adversely impact human health and ecosystems by disrupting endocrine systems. This has led to the development and implementation of various in vivo and in vitro test guidelines to evaluate chemicals for their endocrine disrupting (ED) potential. Currently, guidelines for in vitro tests are focusing on estrogen, androgen and steroidogenesis related endpoints while for other pathways, such as the thyroid hormone signaling pathway, no validated test guidelines are available. Since the thyroid hormone pathway is very complex, various endpoint specific in vitro tests should be employed to cover the complete pathway. In the current presentation, the status in the field of thyroid hormone disruptor testing as well as strategies and tools available for evaluating thyroid hormone disruption in vitro will be discussed.

Scientific Poster

• Non-animal Skin Sensitization Testing Under REACH

Blog

• The EU's New Rules to Identify Endocrine Disrupting Chemicals

Webinar

• Evaluating the Endocrine Disrupting Potential of Your Active Substance

Technical Sheets

• In Vitro Sciences Facilities and Capabilities
• Advanced In Vitro Models
• In Vitro Dermal Penetration
• In Vitro Inhalation
• Endocrine Disruptor Testing Services
• Drug Metabolism Overview