  Traditional animal testing for toxicity is expensive, time consuming,
ethically questioned, sometimes inaccurate because of the necessity to
extrapolate from animal to human, and in most cases not formally validated
according to modern standards. This is driving regulatory bodies and companies
in backing alternative methods focusing on in silico and in vitro approaches.
These are complex to implement and validate, and their wide adoption is not yet
established despite legal directives providing an imperative. It is difficult
to link a cell level response to effects on a whole organism, but the advances
in high-throughput toxicogenomics towards elucidating the mechanism of action
of substances are gradually reducing this gap and fostering the adoption of
Next Generation Safety Assessment approaches. Quantitative in vitro to in vivo
extrapolation (QIVIVE) methods hold the promise to reveal how to use in vitro
-omics data to predict the potential for in vivo toxicity. They could improve
lead compounds prioritisation, reduce time and costs, also in numbers of animal
lives, and help with the complexity of extrapolating between species. We
provide a description of QIVIVE state of the art, including how the problems of
dosing and timing are being approached, how in silico simulation can take into
account the variability of individuals, and how multiple techniques can be
integrated to face complex tasks like the prediction of long term toxicity,
including a close look into the open problems and challenges ahead.
