Environmental Factor – September 2022: Making connections to reduce the use of animals in chemical safety testing

According to Clemens Wittwehr, reducing the use of animals in chemical safety testing will be achieved by establishing links: between chemicals and their toxic effects, between different data repositories and between different groups of people interested in promoting alternatives to animal testing. He feels in an ideal position to make these connections.

“I’m not a life scientist, but I’ve been working with life scientists for ages,” he remarked. “I see myself as the missing link between computer scientists and life scientists, and between scientists and regulators.”

Wittwehr is the Head of the Competence Group for Knowledge Sharing within the Chemical Safety and Alternative Methods Unit of the Joint Research Center (JRC) of the European Commission. He is visiting Research Triangle Park this summer to strengthen the JRC’s ongoing collaborations with the National Toxicology Program (NTP) Interagency Center for Evaluation of Alternative Methods (NICEATM) to advance alternatives to animal testing ( see box).

Wittwehr maintains the Organization for Economic Co-operation and Development’s AOP (Adverse Outcome Pathway) Knowledge Base, a web-based resource that brings together information on how chemicals can induce adverse effects and provides a focal point for development of the PDO. (Photo courtesy of CCR)

“The JRC’s visiting scholar program sends people out to connect with other parties,” he explained. “I hope my time here will support better collaborations between European and US regulators to promote the adoption of alternatives to animal testing.”

Sharing and communicating knowledge is key

Scientific evidence supports the validity of non-animal approaches to predicting chemical effects, according to Wittwehr. However, he is concerned that this knowledge is not being shared and communicated in a way that supports acceptance in a regulatory context.

Wittwehr and his co-authors expressed this concern in the recent JRC report, “Addressing Evidence Needs in Chemicals Policy and Regulation”. The report identifies barriers to acceptance of non-animal methods, including mistrust between stakeholders in different sectors and a lack of consensus on how to use data as evidence for chemical safety regulatory decisions.

“The pandemic has shown us how important it is both to use good science as the basis for policy and to effectively communicate the validity of that science,” he commented. “We have to get it right if we are to replace animals for chemical safety testing.”

The JRC report suggests that confidence in new approaches to chemical safety testing will be supported by the development of knowledge management systems to share, visualize and provide context for chemical safety data. This summer, Wittwehr is receiving input from NIEHS data scientists on the development of these knowledge management systems.

Linking test methods to toxic effects

The concept of the adverse effect pathway, or AOP, is central to using non-animal approaches to predict toxic chemical effects. An AOP is a model of the sequence of molecular, cellular, tissue, organ, organismal, or even population-level events required to produce a toxic effect after exposure to a chemical.

Non-animal test methods measure the effects of interactions between chemicals and cells or biomolecules. A test method that reports on a key event within an AOP can be combined with test methods that report on other key events within the AOP to create a test strategy for a toxic effect. Such testing strategies have been shown to predict toxic effects as well as animal testing.

During his visit to North Carolina, Wittwehr created and leads the Methods2AOP initiative, which explores how to strengthen the links between test methods and key events within AOPs. This can be accomplished through standardized reporting of test method descriptions and results, and documentation that clearly communicates what the test method measures.

“This summer, I’m working with NICEATM data scientists to better align the National Toxicology Program’s Integrated Chemical Environment data with standard reporting templates,” Wittwehr noted. Resources such as the Harmonized Model 201, published by the Organization for Economic Co-operation and Development (OECD), can strengthen the link between a measurement by a test method and a biological effect induced by chemical toxicity.

NICETM Acting Director Nicole Kleinstreuer, Ph.D., welcomed the opportunity to collaborate with Wittwehr. “Within a few months, he has done excellent work with collaborators at NIEHS and the U.S. Environmental Protection Agency to help the United States participate in global efforts to standardize and enforce reporting templates for the mechanistic information of in vitro testing,” she said.

Wittwehr is also exploring how other types of data, such as pathological observations, can be linked to key AOP events. He is collaborating with Brian Berridge, DVM, Ph.D., science director of the NIEHS Division of the National Toxicology Program, and other scientists in the division to link this data to an AOP for cardiotoxicity. “Hopefully we can use this as a test case to demonstrate the value of AOPs to pathologists,” Wittwehr noted.

Wittwehr expects the work he is doing this summer to have an impact beyond the Joint Research Center and NIEHS. He will report on the progress of the Methods2AOP initiative at a meeting this fall at the OECD. Decisions made within the OECD affect regulatory activities in its 38 member countries.

(Catherine Sprankle is a communications specialist for Inotiv, the contractor behind NICETM.)