Mapping the Human Toxome by Systems Toxicology

Abstract

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which human beings are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key pathways, referred as pathways of toxicity, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast “storehouses” of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are more predictive of human toxicity than current methods. The NIH Transformative Research Grant project Mapping the Human Toxome by Systems Toxicology aims at developing the tools for pathway mapping, annotation and validation as well as the respective knowledge base to share this information.

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

“…From technology viewpoint, studies of normal and transformed cell line models in vitro are central to both cancer biology and toxicology work, paving the way to increasing application of cell models as alternatives to animal-based experiments ( fig. 1) [4,9,11,17,18]. Tumour cells are generally more easily grown in vitro than normal tissue cell lines, but both are central to the cancer biology and toxicology disciplines, as both require information of the normal state as reference to the transformed state [16][17][18][19][20].…”

“…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.…”

“…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].…”

Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or “up-shit-creek without a paddle”?

“…1). Academic concepts such as the toxome (http://humantoxome.com/) address this issue by using the tools of molecular biology, cell biology and systems biology to dissect cellular adversity (Bouhifd et al 2014;Hartung and McBride 2011). Scientifically, this is unarguably the most consequent approach.…”