EU Science Hub

How do chemicals cause acute oral toxicity via organ-specific mechanisms?

Sep 28 2018

JRC scientists collected and analysed mechanistic information on the effects of chemicals on eight organs identified as relevant for acute systemic toxicity in humans. The ultimate aim is the replacement of the use of animals in the regulatory assessment of acute oral toxicity.

This knowledge is expected to support the development and application of adverse outcome pathways (AOPs) and mechanistically relevant new approach assessment methodologies.

The replacement of animals in acute systemic toxicity testing, which is a core component of the safety assessment of substances, remains a considerable challenge.

This is partially due to the incomplete mechanistic understanding of the key acute toxicity pathways in humans, some of which are specific for different cell types (e.g. neuronal, cardiac, liver or kidney), while others are broadly applicable (e.g. general cytotoxicity). Therefore, improving the knowledge of the numerous mechanisms involved would be useful to developers of test methods and other predictive tools as well as to validation and regulatory bodies.

Scientists from the JRC hosted EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) analysed the relevant literature and confirmed that general cytotoxicity is an important determinant of acute systemic toxicity.

While the nervous and the cardiovascular systems are the most frequent targets, a clear pattern was not found with regard to which specific mechanisms of target organ toxicity are representative of compounds in the different potency classes.

For this analysis, the potency classes were based on the EU regulatory system for classifying chemicals for acute oral toxicity, namely the Classification, Labelling and Packaging (CLP) categories.

At present, the regulatory classification is based on animal (mainly rodent) studies. Building on all the collected information it is worth trying to develop an alternative way of classifying chemicals for acute oral toxicity based mainly on cytotoxicity and kinetic information, and complemented, if needed, with relevant organ-specific mechanisms of toxicity.

This JRC study provides the relevant information to further develop adverse outcome pathways (AOPs) for better risk assessment of chemicals.

Read more in: Prieto et al. "Investigating cell type specific mechanisms contributing to acute oral toxicity". Altex, 2018 doi:10.14573/altex.1805181

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