The Human Toxome Project

Abstract

SummaryThe Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectrometry-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies.

The need for strategic development of safety sciences

“…Noteworthy, while originally developed in the context of environmental chemical safety, the concept increasingly impacts on drug safety testing (Hartung, 2016b). -The Human Toxome Project 15 (Bouhifd et al, 2015) aims primarily to support the evolution of toxicology towards a mechanism-based science. CAAT, with one of the authors (TH) as principal investigator, promotes the use of advanced-omics and high-throughput technologies and supports the implementation of knowledge-based frameworks such as Pathways of Toxicity and Adverse Outcome Pathways (Hartung and McBride, 2011) and thus plays a key role in implementing the NAS Tox21 vision.…”

Evolution of toxicological science: the need for change

“…New approaches are emerging, under the banner of 'Toxicology for the 21st Century,' that rely on molecular pathways of human toxicity. These include activities for implementing the 2007 NRC report on Toxicity Testing for the 21st Century: A Vision and a Strategy such as the Hamner case study approach (Andersen et al, 2011), the EPAs ToxCast program (http://www.epa.gov/ncct/toxcast/), as well as the US multi-agency alliance Tox21 (http://www.ncats.nih.gov/research/reengineering/tox21/ tox21.html), which test thousands of substances in high-throughput screening assays and make the highly quality-controlled data publicly available, or the NIH Human Toxome project (Hartung and McBride, 2011;Bouhifd et al, 2015), which is beginning to map PoT in a systematic manner. On the European side, a number of projects, most prominently SEURAT-1 (Gocht et al, 2015), aim to develop the use of novel technologies for a variety of toxicological applications; the differences in approach have been characterised earlier (Hartung, 2010e).…”

Challenges and opportunities in the risk assessment of existing substances in Canada: lessons learned from the international community

“…The Human Toxome Project headed by Hartung aims to comprehensively map molecular pathways of toxicity (PoT), defined by cellular processes shown to mediate adverse outcomes, for endocrine disruption using complementary omics approaches such as metabolomics, transcriptomics, and proteomics (Hartung and McBride, 2011). Bouhifd et al (2015) outline a series of eight challenges that have to be met in order to complete this project.…”

“…A robust scientific basis for environmental health risk assessments would be developed by amalgamating data on mode of action, dose-response, and human exposure-based primarily on in vitro testing, computational systems biology pathway models and expanded use of high-throughput (HT) biomonitoring data, respectively (Krewski et al, 2014). New scientific approaches were also acknowledged in the lectures by Hartung and Meunier, including the added benefit of reducing the use of animal models for testing (Schoeters, 2010;Hartung and McBride, 2011;Bouhifd et al, 2015). Challenges of researching, validating, accepting and implementing these new approaches in the context of human health risk assessment and regulatory decision-making were discussed throughout the workshop; five key challenges will be highlighted in this paper.…”