A network toxicology approach for mechanistic modelling of nanomaterial hazard and adverse outcomes

Abstract

Hazard assessment is the first step in evaluating the potential adverse effects of chemicals. Traditionally, toxicological assessment has focused on the exposure, overlooking the impact of the exposed system on the observed toxicity. However, systems toxicology emphasises how system properties significantly contribute to the observed response. Hence, systems theory states that interactions store more information than individual elements, leading to the adoption of network based models to represent complex systems in many fields of life sciences. Here, we developed a network-based approach to characterise toxicological responses in the context of a biological system, inferring biological system specific networks. We directly linked molecular alterations to the adverse outcome pathway (AOP) framework, establishing connections with toxicologically relevant phenotypic events. We applied this framework on a dataset including 31 engineered nanomaterials with different physicochemical properties in two different in vitro and one in vivo models and demonstrated how the biological system is the driving force of the observed response. This work highlights the potential of network-based methods to significantly improve our understanding of toxicological mechanisms from a systems biology perspective, guiding the hazard assessment of nanomaterials and other advanced materials.