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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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Picture of video reel, by Coyau / Wikimedia Commons / CC-BY-SA-3.0

AOPs 201: Presentation videos now available

Building on progress since a successful “AOPs 101” seminars at the Society of Toxicology meeting in 2014, and at the World Congress on Alternatives and Animal Use in the Life Sciences in Prague (2014), the Human Toxicology Project Consortium (HTPC) and the Physicians Committee for Responsible Medicine PCRM offered a more advanced seminar at the Society of Toxicology 2015 meeting in San Diego.  The new seminar reviewed the tools and guidance currently available to help users develop and record AOPs, and presented case studies of AOPs in various stages of development to demonstrate the major developmental steps.

Videos of the seminar presentations are available below.  The presentations included:

AOPs: Overview of AOP Development and Introduction to Regulatory Use

  • Catherine Willett, HTPC

The AOP-Knowledgebase, with demos of the AOP Wiki, Effectopedia, and AOP Explorer (+ questions)

  • Ed Perkins, US Army Engineer Research and Development Center
  • Steven Edwards, US EPA
  • Hristo Aladjov, OECD

Aromatase inhibition leading to reproductive dysfunction in fish: A quantitative AOP case study

  • WanYun Cheng, EPA

AOP for Sensitisation of the Respiratory Tract: Current status and regulatory applications

  • Kristie Sullivan, PCRM

AOP Assessment According to OECD Handbook Criteria

  • Bette Meek, University of Ottawa

Note: these videos are also accessible through our AOPs 201 page.

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Report on the SOT Satellite Meeting, “Updates on Activities Related to 21st Century Toxicology and Evidence-based Toxicology”

(Reprinted from the April AltTox Digest; used with permission.)

At the start of this year’s SOT satellite meeting, “Updates on Activities Related to 21st Century Toxicology and Evidence-based Toxicology” (co-sponsored by the Center for Alternatives to Animal Testing [CAAT], the Human Toxicology Project Consortium [HTPC] and the Evidence-based Toxicology Collaboration [EBTC]), co-moderator Thomas Hartung noted that the annual gathering began in 2009 with 12 people in attendance.  This year, at least 80 people attended – an impressive crowd for a meeting that takes place in the final hours of the week-long Society of Toxicology convention. The annual meeting features updates on US and EU programs and projects dedicated to advancing the toxicity-testing paradigm outlined in the NRC’s 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy.

Richard Paules (US National Toxicology Program) started the presentations with a report on progress in the interagency Tox21 program. The program has moved into Phase III, during which they will be increasing the use of computer models for in vitro to in vivo extrapolation, adding new cell lines, expanding the pathway coverage and human relevance of assays, and developing a high-throughput (HT) transcriptomics platform.

Rusty Thomas (US Environmental Protection Agency) then described a number of initiatives underway in the ToxCast program, including research to develop the metabolic competence of existing assays, developing new assays for priority targets such as the thyroid, and exploring the use of organotypic cell cultures. ToxCast is also expanding its read-across program (and recently hired AltTox Editorial Board member Grace Patlewicz to spearhead that effort).

David Dix (US Environmental Protection Agency) gave an overview of the progress in the EPA’s Endocrine Disruptor Screening Program (EDSP), noting that improved technologies are greatly accelerating the project. The agency is concentrating on building user confidence in its screening battery and expanding the use of computational modeling. (Read an introduction to the EDSP in this two-part In the Spotlight article.)

Melvin Andersen (Hamner Institutes), a co-author of the NRC’s 2007 report, noted that considerable technical and scientific progress has been accomplished in the 8 years since publication of the NRC’s recommendations. Several key pathways have been well-described, and others are under construction. The new challenge is to determine how to communicate this progress to the public, and build their confidence in these methods.

Mark Cronin (Liverpool John Moores University) then provided an overview and update on the six components of the EU’s SEURAT-1 program. (Read more about the SEURAT-1 program in this New Perspective article.) A number of useful tools are coming out of this project, but the key outputs are proof-of-concept case studies. Level 1 studies are designed to demonstrate methods for consolidating existing knowledge to describe key adverse outcome pathways (AOPs). Level 2 studies demonstrate the integration of in vitro and in silico tools to generate predictive models. Level 3 studies, to be finalized later this year, will demonstrate how these models and knowledge bases can be used in quantitative and read-across-based risk assessment and decision-making.

Thomas Hartung reported on the activities of CAAT. Among many initiatives, CAAT is developing a read-across program that aims to facilitate 2018 REACH registrations. CAAT has also been coordinating a series of workshops in Europe and the US to advance “green toxicology” – using in silico tools to design safer chemicals. Filling in for scheduled presenter Marty Stephens, Hartung also described the work of the EBTC, which has been developing and promoting the methods and uses of systematic review in toxicology. Hartung noted that evidence-based toxicology stands to advance twenty-first century toxicology in several ways, including providing a means of assessing the quality of legacy data and new assays, providing guidance on integrating data sources, and ultimately using this information to facilitate validation procedures.

Catherine Willett updated the group on HTPC activities. Willett explained that the HTPC focuses its efforts on three areas: contributing to the advance of relevant science by sponsoring workshops and seminars, lobbying in the US and EU to increase funding for key government initiatives, and developing communication strategies to encourage regulatory and public acceptance of the NRC’s testing strategy. In the last year, the group has especially concentrated on this third area, developing an informative graphic and a series of videos that will be posted on the group’s website later this year. She noted that the HTPC also co-sponsored a seminar at SOT this year – “AOPs 201,” which covered the development and use of AOPs for regulatory purposes. Videos from the seminar will be shared on the group’s website.

The meeting closed with its traditional “open mic” segment – inviting short presentations or discussion questions from those in attendance. The update meeting will convene again at the end of next year’s SOT convention in New Orleans.

(Registered participants of the meeting will be able to access presentation slides on the EBTC website.)

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HTPC co-sponsoring two events at the Society of Toxicology annual meeting in San Diego

The Human Toxicology Project Consortium will once again co-sponsor two ancillary events at the Society of Toxicology’s annual meeting in San Diego in March.

Along with the Physicians Committee for Responsible Medicine, we’re excited to expand the popular AOPs 101 series with a new workshop: “AOPs 201”: A Seminar on Development, Recording, and Use of Adverse Outcome Pathways.  This event will take place Monday, March 23, from 5:00 PM–7:30 PM (local time) at the San Diego Marriott Marquis & Marina in Marina Ballroom F.

Then on March 26, we’ll join HTPC partner Center for Alternatives to Animal Testing and the Human Toxome Project in co-sponsoring the annual satellite meeting, Updates on Activities Related to 21st Century Toxicology and Evidence-based Toxicology: Invited Presentations and Open Microphone.  This event will be held in the Hillcrest Room of the Manchester Grand Hyatt in San Diego, from 12:30 to 4:00 PM (local time).  Invited speakers and topics include:

  • Richard Paules (US National Toxicology Program) – Tox21 Update
  • Russell Thomas (US Environmental Protection Agency) – ToxCast Update
  • David Dix (US Environmental Protection Agency) – EDSP21 Update
  • Melvin Andersen (Hamner Institutes) – Hamner TT21C Update
  • Mark Cronin (Liverpool John Moores University) – SEURAT Update
  • Thomas Hartung (Johns Hopkins) – CAAT’s Read-across Initiative and Human Toxome-related Activity Update
  • Catherine Willett (HTPC) – Human Toxicology Project Consortium Update
  • Martin Stephens (Johns Hopkins) – Evidence-based Toxicology Update

For those planning to attend SOT 2015, more information about this satellite meeting is available here (the event is free; box lunches will be provided to pre-registrants).

AOPs Meetings & Events

Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science

…SeqAPASS provides us with a fast, efficient screening tool. Using it, we can begin to extrapolate toxicity information from a few model organisms (like mice, rats, zebrafish, etc.) to thousands of other non-target species to evaluate potential chemical susceptibility.

SeqAPASS provides an example of how EPA Chemical Safety for Sustainability researchers are leading the effort to usher in a new generation of toxicology practices that aspire to reduce the number of animals used, decrease costs, and increase the efficiency of chemical toxicity testing. The 21st century chemical toxicity testing strategy incorporates these ideals and has given rise to adverse outcome pathway (AOP) development and rapid, high-throughput chemical screening programs such as EPA’s ToxCast program.

Read more on the EPA’s science blog: Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science.

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Male thyroid anatomy

Paper encouraging non-animal approaches to metabolism wins award

Among the awards bestowed at the 9th World Congress for Alternatives and Animal Use in the Life Sciences in August, a paper co-authored by consortium director Catherine Willett was named the journal ALTEX’s “Best ALTEX article of 2013.”

In vitro Metabolism and Bioavailability Tests for Endocrine Active Substances: What is Needed Next for Regulatory Purposes?” by Miriam N. Jacobs, Susan C. Laws, Kate Willett, Pat Schmieder, Jenny Odum, and Toine F. Bovee, revisits and expands on recommendations put forth in a 2008 OECD review paper that argued for the assessment of human metabolism in in vitro assays used to screen endocrine-active substances.  Although that earlier paper showed that many of the necessary screening tools were already available, little progress has been made by the European, US, or Japanese validation agencies toward validating such methods for use in a regulatory context.  In the ALTEX paper, Jacobs et al. outline a series of projects designed to accelerate validation, continue to expand the number of available metabolism-enhanced screening assays, and improve and expand predictive tools.


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