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Environmental Factor, March 2013

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Speaker calls for crowdsourcing to advance predictive toxicology

By Laura Hall

Maurice Whelan, Ph.D.

"The way I see it, is most of the knowledge we need exists. It exists in your heads," said Whelan, to his mostly NTP audience, as he discussed the knowledge requirements of AOPs. (Photo courtesy of Steve McCaw)

Raymond Tice, Ph.D.

Tice expressed his interest in the AOP concept. "This approach should allow us to accelerate the identification of alternative assays that will be useful for predicting the ability of environmental compounds to pose a hazard to humans." (Photo courtesy of Steve McCaw)

Guest lecturer Maurice Whelan, Ph.D., discussed the implications of a European ban on animal testing of cosmetics for chemical risk assessment during a Jan. 29 talk at NIEHS. Whelan is head of both the Systems Toxicology Unit and European Union (EU) Reference Laboratory for Alternatives to Animal Testing at the EU Joint Research Centre.

"On March 11, 2013, the marketing ban will be enforced in Europe for cosmetics tested on animals," Whelan explained. "No chemical explicitly for use as a cosmetic ingredient should be tested on an animal after that date, anywhere in the world." Cosmetics companies are, therefore, faced with a considerable challenge – how to ensure product safety when validated alternative methods that cover the spectrum of relevant adverse health effects are simply not available.

Whelan’s group has been given a broad mandate — “Bridge the gap between what is coming out of research and what we need to deliver to decision-makers," he said. What’s needed is a determined shift toward a safety assessment paradigm that relies on understanding toxicity, rather than simply observing its effects.

Typically, toxicological evidence comes in the form of observational data on endpoints derived from animal tests, which often lack sufficient indication of underlying causes. This shortcoming presents a major obstacle in the development of alternatives, since searching for blind correlations between in vitro and in vivo assays is insufficient.

As Whelan explained, only by shifting to a knowledge-based paradigm for chemical safety assessment, will scientists be able to save resources, avoid the use of animals, and ultimately provide better risk predictions relevant to humans. As one useful means to achieve these goals, Whelan presented what is known as the adverse outcome pathway (AOP) framework.

Adverse Outcome Pathway

“An AOP is what engineers would call a mode of failure — the sequence of events that leads to system failure or dysfunction," said Whelan. It is an analytical tool captured in a template that is defined by two anchors — an initiating event at the biological-chemical interface and, at the other end, an adverse outcome. In between is a chain of events that are manifest at the molecular, cellular, tissue, organ, and organism levels — a causal flow linking an initial insult to an adverse health effect. The AOP paradigm allows profiling a chemical by its potential to trigger an initiating event, as opposed to its association with an endpoint, Whelan added.

Developing an AOP requires knowledge of the underlying biological mechanisms, and how sufficiently perturbing normal function results in dysregulation and, ultimately, toxicity. The fact that there can be areas within the chain of events that are unknown helps focus attention on what research needs to be done for a fuller understanding. Whelan said he is convinced we have most of the knowledge needed, but conceded, "We have done a terrible job of distilling it down, of being explicit in what we know and how we can use it."


As co-chair of the Advisory Group on Molecular Screening and Toxicogenomics of the Organisation for Economic Co-operation and Development (OECD), Whelan is heavily involved in the OECD's AOP development program, which was officially launched in January. He argued that its success will depend on implementing a crowdsourcing model to ensure that the widest community of experts can contribute to AOP development and evaluation.

"It starts today," he said. The process will continue through communications like this talk and through various web-based media. "We want to put all of this knowledge in one place, so that people can contribute online, can evaluate online, and really exploit the community model," explained Whelan.

Whelan’s proposals sparked questions and discussion among the audience at the seminar, which was hosted by Raymond Tice, Ph.D., head of the NTP Biomolecular Screening Branch.

(Laura Hall is a biologist in the Program Operations Branch of the Division of the National Toxicology Program.)

Michael DeVito, Ph.D.

During the discussion, Michael DeVito, Ph.D., left, head of the NTP Experimental Toxicology Group, said, "The advantage of this approach is that it is actually forcing you to quantitatively and qualitatively describe what you think is happening." (Photo courtesy of Steve McCaw)

AOP Graphic

Example of modular units of an AOP template (Photo courtesy of Maurice Whelan)

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