Aldert H. Piersma*, Harm Heusinkveld, Ellen Hessel and Anne Kienhuis
The innovation of chemical hazard and risk assessment based on in vitro and in silico modeling of human biology and toxicology is rapidly gaining momentum. Whilst animal studies have been the core basis of chemical safety evaluations for half a century, a wealth of animal-free alternative assays have been developed during that same period but have only scarcely gained implementation in the regulatory arena. The reductionist nature of such as says, and the intent towards one to one replacements of animal studies by alternative assays have limited progress in this area. This paper advocates a human based holistic approach to chemical safety assessment, based on an in silico description of human biology, the derivation of the adverse outcome pathway network from that description, its translation into batteries of in vitro and in silico assays to monitor critical key events in the pathway network, and the integration of the results by modern computational tools to predict health effects. Several ongoing international research projects are described which take on this challenge aiming at providing proofs of principle for the feasibility of this approach. This advance is supported by successes of the application of machine learning in clinical diagnostics and treatment. Crucial elements include the need for quantitative data integration, the management of large scale databases, and overall, the comprehensiveness of the testing strategy as to the coverage of the adverse outcome pathway network represented in the in silico system. Apart from the scientific innovation to human safety assessment, the ethical aspect of avoiding the detour of the animal study for determining human safety is an important additional gain of the human based approach. Whilst this innovation meets with practical challenges and possible pitfalls, it takes advantage of rapidly growing computational opportunities and in due course is expected to significantly benefit human health protection.
