Systems Toxicology: From Basic Research to Risk Assessment

Abstract

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment.

Incorporating evolutionary insights to improve ecotoxicology for freshwater species

“…Multidisciplinary perspectives and techniques, for example from genetics, physiology, and ecology, have yielded a robust understanding of toxicological outcomes and mechanisms across levels of biological organization, from molecular processes to population‐level and community‐level consequences (Peterson et al., 2003; Sturla et al., 2014; Whitehead, Pilcher, Champlin, & Nacci, 2012). Indeed, efforts aimed at understanding how molecular impacts of contaminants shape ecological outcomes have become a recent focus of ecotoxicology (e.g., “adverse outcome pathways,” Ankley et al., 2010).…”

Cancer Biology, Toxicology and Alternative Methods Development Go Hand‐in‐Hand

“…Considering databases, the large repositories of clinical cancer data, including genomics analyses of tumours and bioinformatics tools, provide templates for what is also increasingly explored in the toxicological sciences [24]. Biomarker discovery in cancer uses data patterns for prediction of patient cancer prognosis, responsiveness to therapy or cancer proneness; it has its counterpart in toxicology where the aim is to understand the mass/number of genes which make up 'the toxome' (genes and pathways causatively involved in toxicity effects) or which have application for modelling how specific toxicity effects can be predicted with subsets of the toxome [10,11,13,[25][26][27]. Thus, for transforming and modernizing toxicology, the usefulness of considering following in the footsteps of the extensive thrust of output generated in other sciences, and especially cancer research, is likely extensive.…”

“…Typically, the gene expression profiling analysis of stage 3 would serve to determine broad toxicology-relevant bioidentities of 'the selected few' group. Such work includes the exploration or verification of novel or known pathways of toxicity, MoA mechanisms and in a broader sense, adverse outcome pathways (AOP) [2,4,5,[11][12][13]31,32]. Expanded testing regimes might naturally apply a wider range of cell types and assays, including the consideration of low-dose effects and application of differentiated, metabolically competent cell models [6,7,19,33,34].…”

“…A constantly increasing number of chemicals and engineered nanomaterials (ENMs) emphasize the need of applying novel tools and screening technologies outside of the standard, both lengthy and expensive, rodent toxicological tests traditionally used in such work [1][2][3][4][5][6][7][8][9][10][11][12][13]. Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12].…”

“…Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12]. Summarized under a concept termed 'Toxicity Testing in the 21st Century' or 'Tox21', biochemical and cell-based in vitro assays coupled with bioinformatics and modelling-driven in silico assays are now considered key to transforming toxicology from a previously animal-based testing practice into a computational science built on systems biology [2,4,6,[9][10][11]13]. The resulting novel research field is variably termed 'systems toxicology', 'toxicogenomics' or 'computational toxicology' [3,4,8,14,15].…”