Integrated Testing Strategy (ITS) e nuove tecnologie nella sostituzione dei test su animali per la valutazione del rischio di sostanze chimiche, cosmetici e farmaci

[Leist M, Lidbury BA, Yang C, Hayden PJ, Kelm JM, Ringeissen S, Detroyer A, Meunier JR, Rathman JF, Jackson GR Jr, Stolper G, Hasiwa N. Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics, and drugs with animal-free methods. ALTEX. 2012;29(4):373-88.]

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Several alternative methods to replace animal experiments have been accepted by legal bodies. An even larger number of tests are under development or already in use for non-regulatory applications or for the generation of information stored in proprietary knowledge bases. The next step for the use of the different in vitro methods is their combination into integrated testing strategies (ITS) to get closer to the overall goal of predictive “in vitro-based risk evaluation processes.” We introduce here a conceptual framework as the basis for future ITS and their use for risk evaluation without animal experiments. The framework allows incorporation of both individual tests and already integrated approaches. Illustrative examples for elements to be incorporated are drawn from the session “Innovative technologies” at the 8th World Congress on Alternatives and Animal Use in the Life Sciences, held in Montreal, 2011. For instance, LUHMES cells (conditionally immortalized human neurons) were presented as an example for a 2D cell system. The novel 3D platform developed by InSphero was chosen as an example for the design and use of scaffold-free, organotypic microtissues.The identification of critical pathways of toxicity (PoT) may be facilitated by approaches exemplified by the MatTek 3D model for human epithelial tissues with engineered toxicological reporter functions. The important role of in silico methods and of modeling based on various pre-existing data is demonstrated by Altamira’s comprehensive approach to predicting a molecule’s potential for skin irritancy. A final example demonstrates how natural variation in human genetics may be overcome using data analytic (pattern recognition) techniques borrowed from computer science and statistics. The overall hazard and risk assessment strategy integrating these different examples has been compiled in a graphical work flow.


Each of the technical approaches and model systems presented here has been developed as a stand-alone method. Most have been developed for a specific purpose and to solve defined problems. Dozens, if not hundreds, of such technologies are already available, and only a few have been picked to exemplify the progress in the field. We have put forward the hypothesis here that added value may be generated by a combination of such approaches. The approach taken here may, at first glance, look different from or in competition with other new strategies. For instance, the ToxCast program, or different approaches that follow the “Tox21″ vision take a different starting point. In their extreme form, they rid themselves of the old patchwork of different toxicological models, be they in vivo or in vitro, and put forward a new homogeneous framework, based, for instance, on PoTand systems biology modeling. It is not yet clear, which role assays play that use endpoints that are toxicologically apparently simple but (systems-) biologically highly complex, e.g., cell death, neurite degeneration, or albumin secretion. Here we take an alternative approach to define an overall scaffold of what information would contribute to an animal-free risk assessment. This scaffold is used to recruit a largely heterogeneous group of assays, providing information at different levels of complexity, with different throughput rates, and possibly with different information value. Combined in a scheme, these assays can fill knowledge gaps and improve the overall risk assessment of chemicals for which little is known. The framework suggested here is also suited to the incorporation of individual tests and in silico methods developed for Tox21, or even to incorporation of testing strategies at a higher level of integration, as shown by the Altamira example of skin irritancy modeling. Thus, this approach may represent a practical solution for high production volume risk assessment in the intermediate future, while many tests are still under development and no complete test platform on the basis of PoTtesting is available. The future will then bring higher throughput assays, better systems biology modeling, better integration of data from omics technologies, and better cell sources. For instance, we envisage that testing in non-transformed cell models, of murine or preferentially of human origin, will require a further development of stem cell technology, to provide reliable cell sources.



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