Overview

Developmental and adult neurotoxicity describe harmful effects on the developing or mature nervous system. They are currently assessed using specific studies and according to international guidelines ↗, such as those from the Organisation for Economic Co-operation and Development (OECD ↗). These guideline studies require significant resources, making them impractical for evaluating adverse effects of large numbers of chemicals. Because of this, there is an international agreement ↗ that testing for developmental neurotoxicity needs to be faster and more directly relevant to humans. To achieve this, experts are working to replace traditional methods with a group of new, more efficient tests designed for regulatory purposes.  

The current state-of-the-art involves a set of lab-based experiments called the Developmental Neurotoxicity in vitro test battery ↗ which use cells from humans and rats to study important processes in brain development. While this is a major step towards establishing an alternative testing regime, there are still gaps in the kinds of effects these tests can detect. The main goal of this project is to fill those gaps.  

To improve the current testing battery and create a system for testing effects on adult brains, this project will focus on three major tools: i) human cells, which avoid difference between species, (ii) zebrafish embryos, which are useful because they contain a complete nervous system capable of performing complex behaviours that could potentially be disrupted by chemical exposure, and (iii) computer-based methods that use models to predict neurotoxic effects.  

New Approach Methodologies (NAMs ↗) will look at areas that have not been fully explored before, such as:  

• How disruptions in hormone systems (endocrine disruption ↗), gene activity (transcriptomics), and long-term genetic regulation (epigenetics) affect brain development,  
• The formation and function of brain connections (synaptogenesis and neural networks),  
• The development of the blood-brain barrier (a protective layer in the brain),  
• Behavioural effects like reflex responses (startle), anxiety-like behaviour, and learning and memory.  

Achievements & Results

A joint paper ↗ identifies key research gaps that this project aims to address, providing a framework for advancing toxicological understanding. 

One study ↗ explored genes essential for brain development, including those involved in forming neural connections, maturing different types of brain cells, and responding to hormone-disrupting chemicals. 

A series of two papers in early life stage zebrafish show that you can rapidly identify the mechanisms by which environmental chemicals disrupt behaviors such as learning (PubMed ↗) and startle responses (PubMed ↗; BioRxiv ↗), and that these mechanisms are conserved in rodent and human cell based models. This builds confidence in the use of zebrafish-based NAMs to predict human neurotoxicity effects.

Another key PARC 5.2.1e study advances developmental neurotoxicity testing by providing new data-driven insights relevant for regulatory decision-making. Access the full paper here ↗.

Finally, a new model using human-like brain cells, called LUHMES neurons, enables researchers to study nerve damage more effectively. This method allows detailed observation of nerve endings, measurement of specific markers, and analysis of biochemical changes after injury. See the full study here ↗.

Policy relevance

The EU's REACH ↗ regulations mandate comprehensive neurotoxicity testing for chemicals, but traditional methods are resource-intensive and impractical for evaluating large numbers of substances. This project seeks to create faster and more human-relevant testing methods for neurotoxicity, focusing on both developmental and adult effects. It emphasizes lab-based tests that address critical processes in brain development while working to close gaps in existing approaches. The ultimate aim is to recommend these improved methods for inclusion in regulatory testing frameworks.