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A new paper applies pathway biology to disease research and drug discovery

“Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research,” a new paper by a team of international experts including authors from Human Toxicology Project Consortium partners Humane Society International, The Humane Society of the United States, and Unilever, calls for a systems-biology approach to biomedical research and drug discovery. The approach borrows insights from toxicology, where adverse outcome pathways (AOPs) – a framework for documenting the physiological path between chemical exposure and “adverse outcomes” such as illness, injury, or environmental harm – are being used to integrate data from a variety of new scientific technologies. The authors propose that this same framework can be expanded to disease research, and can greatly improve our ability to identify effective drugs and therapeutics.

“…[M]any human illnesses such as cancers, diabetes, immune system and neurodegenerative disorders, and respiratory and cardiovascular diseases are caused by a complicated interplay between multiple genetic and environmental factors,” the authors write. Technology developments over the last two decades have made it possible to measure how genes determine our susceptibility to diseases, as well as how genes, proteins, cells, and tissues react to various environmental exposures. Application of such developments to drug discovery “require(s) a new research paradigm to unlock their full potential.” Just as AOPs integrate these new types of information to help reveal toxicity mechanisms and protect people and the environment from potential effects of chemical exposure, disease pathways can be used to understand risk and disease mechanisms, leading to more effective cures. According to the authors, “The disease AOP approach would better exploit advanced experimental and computational platforms for knowledge discovery, since the emergence of AOP networks will identify knowledge gaps and steer investigations accordingly.”

Progress in disease research and drug discovery has been slow, the authors say, because of continued reliance on inappropriate and unproductive animal models. The AOP framework encourages the use of emerging human-specific cell- and tissue-based models – such as 3D tissue constructs and organs-on-chips – combined with increasingly advanced computational models. The powerful combination can accelerate our understanding of disease, while reducing the use of animals.

The paper was published in the open access journal, Environmental Health Perspectives: http://ehp.niehs.nih.gov/wp-content/uploads/123/11/ehp.1510345.alt.pdf

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China developing a roadmap to twenty-first century toxicity testing

At a special symposium last month in Xi’an, China, participants began to map China’s regulatory steps toward twenty-first century toxicology and away from animal testing.

The symposium, “TT21C/AOP China Roadmap,” was part of a conference on alternatives to animal tests in toxicology that was hosted by the Chinese Society of Toxicology’s Committee on Toxicological Alternatives and Translational Toxicology and the Chinese Environment Mutagen Society’s Committee on Toxicity Testing and Alternative Methods, and co-sponsored by the Humane Society International (HSI), Unilever, L’Oreal, and Shell. The symposium was convened “to address the need to increase Chinese regulatory uptake of currently available alternatives and the AOP paradigm.” Human Toxicology Project Consortium coordinator Dr. Catherine Willett was an invited speaker (a PDF of her presentation, “Use of Adverse Outcome Pathways (AOPs) to Reduce Uncertainty and Animal Use in Chemical Hazard and Risk Assessment,” is available).

During the symposium, a working team comprised of members from the host societies and representatives from Unilever, L’Oreal, HSI, and others was established to begin working on the twenty-first century toxicology “roadmap.” Asked about the team’s next steps in a Chemical Watch article (subscription required) about the symposium, Dr. Carl Westmoreland (Director of Science and Technology at Unilever’s Safety and Environmental Assurance Centre, and a member of the working team) said the host committees will prepare a summary of the proceedings and circulate it to participants for review.

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HTPC member Unilever partners with the EPA to develop non-animal approaches to safety testing

Human Toxicology Project Consortium member Unilever announced Tuesday that it will be collaborating with the US Environmental Protection Agency on a project that will improve and advance human-relevant chemical safety assessment while phasing out the use of animals.

The project will create case studies around chemicals of mutual interest, using existing data from the Toxcast and Tox21 programs combined with Unilever’s data and methods for estimating consumer exposures, and testing new high-throughput screening methods that account for metabolism and more completely assess human biological pathways.

Quoted in the joint press release, Russell Thomas, Director of EPA’s National Center for Computational Toxicology, said that if the project is successful, “research from this collaboration will result in better ways to evaluate the potential human health effects of new ingredients and chemicals we currently know little about. …These methods could be used by both industry and governmental agencies to reduce the costs associated with safety testing and accelerate the pace of chemical risk assessment.” And Julia Fentem, Vice President of Unilever’s Safety and Environmental Assurance Centre, said, “This research collaboration is strategically very important for Unilever’s long-held ambition to eliminate the need for any animal testing while also continuing to ensure the safety of consumers and our environment. If we had robust scientific tools to accurately and rapidly predict exposures to chemicals at the cellular and molecular levels within the human body, this would be a huge step forward in being able to conduct safety risk assessments without using animal data.”

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Unilever’s pathway-based, non-animal approaches to toxicity testing

A new article by scientists at Unilever, a corporate member of the HTPC, describes several areas of safety science in which they are using a pathway-based approach to replace traditional animal tests with a combination of human cell-based in vitro assays and computational models.  The article, “Toxicity testing – non-animal approaches and safety science” (by Fiona Reynolds, Carl Westmoreland and Julia Fentem) is included in the current issue of The Biochemist: “Replacement in Research” (Vol. 36(3), June 2014).

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