Coordinator: Andre Kleensang (akleens1@jhu.edu)
Human Toxome Project Website (external)
The Human Toxome program aims primarily to support the evolution of toxicology towards a mechanism-based science. CAAT 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) and plays a key role in implementing the NAS Tox21 vision report from 2007.
CAAT is running since 2011 a dedicated metabolomics laboratory equipped with Agilent State-of-the-Art mass spectrometer. This program aims primarily to support the evolution of toxicology towards a mechanism-based science and promotes the use of advanced-omics and high-content technologies and supports the implementation of knowledge-based frameworks (such as pathways of toxicity). (Toxico)metabolomics promises a holistic phenotypic characterization of biological responses to toxicants. A prominent use of metabolomics is the identification of signatures of toxicity - patterns of metabolite changes predictive of a hazard manifestation as well as targeted approaches to measure specific metabolites ("biomarkers") as proxies by which a particular pathological or physiological process, disease, etc. can be identified. Metabolomics use in toxicology is rapidly increasing, particularly owing to advances in mass spectroscopy, which is widely used in the life sciences for phenotyping disease states.
At the moment the program is mainly driven by two funded projects: The NIH Transformative Research Grant “Mapping the Human Toxome by Systems Toxicology” and the EU-ToxRisk project.
1. NIH Transformative Research Grant “Mapping the Human Toxome by Systems Toxicology”
The Mapping the Human Toxome by Systems Toxicology project aims to achieve the following goals:
- Use complementary “omics” approaches (transcriptomics, metabolomics), to map and annotate Pathways of Toxicity (PoT) for a defined set of endocrine disruptors.
- Complete the development of software and visualization tools to enable the integration, analysis and visualization of data across multiple omics hardware platforms.
- Identify Pathways of Toxicity and develop a consensus-driven process for pathway annotation, validation, sharing.
- Validate PoT and extend the PoT concept to additional toxicants.
The project resulted so far in 27 scientific peer-reviewed publications. All manuscripts have been published in in high reputation journals like PLoS, Nature’s Scientific Reports, Anal Chem, ALTEX, Arch Toxicol and Crit Rev Toxicol. This resulted so far in >300 citations and four of the articles are high-impact articles based on citations within three years after publication (>50 each).
2. EU-ToxRisk: An Integrated EUropean ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century
In January 2016, CAAT became a partner the EU-ToxRisk project. EU-ToxRisk is an Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century to support the paradigm shift in human risk assessment, away from the traditional in vivo animal studies towards new approach methodologies (NAMs). EU-ToxRisk with its almost 40 partners and $40 million funding focusses on two areas: repeated dose systemic toxicity, using the lung, kidney, liver and nervous system as examples of potential target organs; and developmental and reproductive toxicity. Even though the development of new non-animal methods is one target of EU-ToxRisk, the project puts special emphasis on their acceptance, implementation and training in regulatory contexts.
CAAT US is an active partner in five Work Packages with main contributions:
- Stakeholder interactions to promote dissemination, uptake and commercialization of results
- Internal training program
- Organization of symposia and satellite meetings
- Algorithm/software/omics analysis development for IATA construction/validation based on previous work on R01 Mapping the Human Toxome
Successful role as honest broker
In February 2019 CAAT organized as two satellite meetings to the Society of Toxicology Annual Meeting (SOT) a follow up EU-ToxRisk meets Tox21c and EU-ToxRisk meets US FDA. Tox21c is a federal collaboration among the US Environmental Protection Agency, the National Institutes of Health, including the National Center for Advancing Translational Sciences and the National Toxicology Program at the National Institute of Environmental Health Sciences, and the US Food and Drug Administration.
In addition, we organized a SOT symposium on the “Strategic development of read-across within the EU-ToxRisk project and beyond”. This symposium provided a view across the Atlantic – an in-depth overview and demonstrate opportunities of the use of read-across, starting with an EU regulatory perspective and then broadening the scope to the most up-to-date developments from the EU-ToxRisk program. A focus was set on read-across case studies, by which the use of NAMs and mechanistic data is demonstrated. While the majority of techniques used within EU-ToxRisk is already well established, the project also invested into the development of new in silico prediction models. In addition, the symposium addressed automated read-across (RASAR—read-across-based structure activity relationships) and Good Read-Across Practices.
