Goal
The goal of OSIRIS is to develop Integrated Testing Strategies (ITS) fit for REACH that make it possible to significantly increase the use of non-testing information for regulatory decision making, and to effectively reduce animal testing to the level needed from a risk perspective.
To this end, operational procedures are developed, tested and disseminated that guide a transparent and scientifically sound evaluation of chemical substances in a risk-driven, context-specific and substance-tailored (RCS) manner, and allow decision making to be built on information-rich combinations of novel non-testing and optimized experimental information.
In this context, a major scientific challenge is to identify, reduce and manage the level of uncertainty. Accordingly, the envisaged decision-theory based framework will be designed to handle uncertainty explicitly, covering data, methods, models and decision making.
Major objectives
The ITS to be developed is based on a targeted exploitation of chemical, exposurerelated and biological information including genomics, guiding REACH testing needs in the context of available non-test information. Accordingly, OSIRIS undertakes distinct research into the scientific scope, level of uncertainty and regulatory applicability of respective non-testing methods and novel mechanism-targeted techniques, and their integration in a decision theory framework.
Five major objectives form the basis for five interlinked research Pillars:
Pillar 1: Chemical Domain
Objective: To develop methods and guidance for transparent and scientifically sound use of chemistry-driven information in ITS.
The methodology of Pillar 1 concerns all non-testing approaches that make use of molecular structure information for predicting fate and effect of chemical substances. It feeds the ITS components read-across, chemical categories (grouping), qualitative and quantitative structure-activity relationships (QSAR) and further in silico (computational chemistry) techniques, and also cut-off triggering to waive experimental testing in case of technical constraints.
Pillar 2: Biological Domain
Objective: To provide efficient strategies and guidance for exploitation of all types of biological information on toxic effects of chemicals in ITS, focusing on reduced animal use and informed extrapolation across human and environmental toxicology, species, endpoints and time scales.
The methodology of Pillar 2 covers chemical and biological read-across (chemical-chemical and species-species extrapolation), in vitro testing, optimization of in vivo protocols and mechanism-targeted genomics, and in silico techniques. It seeks for mechanism-based screens to prioritize chemicals in terms of testing needs across human and ecological endpoints, and addresses uncertainty caused by differences in species sensitivity and through different types of extrapolation.
Pillar 3: Exposure
Objective: To develop criteria for exposure informed testing as foreseen in the REACH regulation, and to refine relevant exposure assessment methods accordingly.
The methodology of Pillar 3 covers exposure-based waiving and triggering of experimental testing. Exposures considered are direct human exposure at the workplace and as consumer and environmental exposure of humans and wildlife, and take into account relevant exposure scenarios including use patterns and conditions of use. Methods for multimedia fate modeling, including bioaccumulation, fate of polar compounds and degradation pathways, and for absorption, distribution, metabolism, excretion (ADME) are made fit for REACH, applying probabilistic techniques to account for uncertainty associated with data and models.
Pillar 4: Integration Strategies and Tools
Objective: To develop weight-of-evidence approaches for ITS based on a computerized decision theory framework ready for web access, optimizing the use of existing data and non-test information, and minimizing the need for new testing in risk assessment procedures.
The methodology of Pillar 4 addresses all existing and possibly new ITS components including thresholds of toxicological concern (TTC) for human and environmental toxicology. A major challenge is the identification, reduction and management of uncertainty associated with data, models, decision making and lack of knowledge. Technical information is combined with stakeholder views from regulatory authorities and industry to build and disseminate a decision theory framework for ITS, taking into account cost-benefit analyses as well as societal risk perception. A web-based tool for ITS will be made publicly available.
Pillar 5: Case Studies
Objective: To evaluate the feasibility and effectiveness of the new ITS methodologies and to provide guidance for their use in concrete form, covering major human and environmental endpoints.
The methodology of Pillar 5 addresses the feasibility and scope of full ITS schemes through comprehensive test applications. It covers human and environmental toxicology, and different exposure routes and chemicals. Cases with complete REACH sets of data provide opportunity for identifying limitations and refinement of ITS. Evaluation of their accuracy, predictivity, savings with respect to animal use, time and costs, and their level of uncertainty as compared to conventional procedures will result in recommendations and guidance for their implementation in REACH.
