S4: Systemic toxicity

Adverse outcome pathways as a mechanistic basis for the development of animal-sparing approaches to assessment of repeat dose systemic toxicity
Session 4: Adverse outcome pathways & assessment of repeat dose systemic toxicity, Euro 2016

Angela Mally


Department of Toxicology, University of Würzburg




While the advesere outcome pathway (AOP) concept has been a key aspect of human cancer risk assessment for some time, it was recently adopted by the OECD as a pragmatic tool which may facilitate transition of chemical safety assessment from measurement of apical endpoints in animals to toxicity prediction based on mechanistic information.

The idea is that identification of key events and systematic mapping of AOPs for a given hazard endpoint can form the basis for the development of alternative tests as part of an integrated testing strategy to eventually replace conventional guideline studies.

The Risk-IT project was initiated to contribute to the development of integrated animal-sparing approaches to assessment of repeat dose systemic toxicity, focussing on kidney toxicity as a sharply-defined, exemplary area of systemic toxicity.  

Risk-IT aims to analyse and integrate quantitative systems-wide molecular changes to establish a causal chain of molecular and cellular events that link chemical exposure to renal toxicity and to inform on the most predictive endpoints indicative of adverse effects.

Risk-IT will then develop an in vitro test battery that covers key events across the developed AOPs and that can be integrated with quantitative in vitro to in vivo extrapolation and exposure modelling to derive quantitative risk estimates.

A key aspect for quantitative toxicity prediction is to understand how well the developed assays reflect these key events as well as understanding the quantitative relationships between upstream and down-stream key events.