ZonMW - ASAT2

Systems toxicology supported data infrastructure for human risk assessment

finalized

At present, animal testing is important to guarantee the safety of drugs, chemicals, cosmetic ingredients and food constituents. At the same time, there is increased societal need for reduction, replacement, or refinement (3R) for animal experimentation, as evidenced for example by political interest (e.g. Actieplan Dierproeven en Alternatieven 2011-2021 and VWS), as well as the attention at EU commission level for 3R (e.g. recent lunch debate with Mr. Prodi MEP). In addition, new legislation has been implemented that aims at reduction of animal testing (Seventh Amendment to the Cosmetics Directive), and companies are beginning to change their product development towards sustainable animal-friendly alternatives.

To assess the safety of pharmaceuticals and chemicals, information on several endpoints is taken into account, including repeated dose toxicity, carcinogenicity, mutagenicity, reproduction toxicity, and sensitization. Hazard identification and characterization is based mainly on rodent models. However, the predictive value of current rodent models is under debate. For example, the accuracy for predicting repeated dose toxicity and carcinogenicity in man is only 60% which contributes to the high attrition rate observed in drug development. This is partially due to interspecies differences in kinetics of the compound, and intrinsic species-specific mechanisms by which compounds exert their possible toxicity. Still, regulatory frameworks demand animal testing for hazard and risk assessment. Moreover, registrants will not accept restrictive measurements for their products on basis of non-legally binding studies.

The ASAT (Assuring Safety Without Animal Testing) concept including kinetics/PBPK modelling is at present based upon one case only (paracetamol). To obtain a better proof-of-principle of the general applicability of this approach, the current ASAT Knowledge base will be further developed following two distinct venues with potential of ultimately leading to regulatory non-animal based applications in future:

• Hepatocellular cancer and liver toxicity, in particular cholestasis, for preclinical toxicity testing for pharmaceuticals.
• Sensitization (ACD), for the development of an international harmonized approach for a non-animal based Intelligent Testing Strategy for hazard assessment. Ultimately, such an ITS may have potential to be implemented in regulatory framework.