ECETOC workshop report sets out steps required to increase acceptance of mathematical modelling in chemical safety assessments

Brussels, 29 September 2022 – Scientific experts at a workshop organised by ECETOC explored how to use mathematical modelling to help extrapolate toxic doses of chemicals found in isolated cell and tissue cultures tested in the lab to expected adverse health responses in live humans and animals, so reducing the need for animal testing in chemical safety assessments. (Read the full article here).

The extent to which a chemical is toxic to humans and animals largely depends on how much of the chemical is absorbed, distributed, metabolised and excreted in the body. Physiologically Based Kinetic (PBK) modelling uses mathematical techniques to quantify and predict the absorption, distribution, metabolism and excretion of a chemical after its exposure to humans or animals.

Although PBK modelling is increasingly used by the scientific community – and several generic PBK platforms are available that all provide similar results when harmonised inputs are used – there are still challenges for EU regulators to accept the models’ predictions for chemical risk assessments.

During the workshop, the scientists therefore proposed several different steps aimed to increase regulators’ confidence in PBK modelling approaches.

First, the contexts and applications in which PBK modelling can be used should be explicitly defined, for example, their use is better accepted in prioritising risk than in establishing reference doses. In human health risk assessments, any lack of data might be addressed if plausible conservative assumptions can be identified. These assumptions must be conservative enough to ensure human health protection.

Second, regulators and the scientific community should agree on the criteria for good-quality model input parameters, especially in the absence of experimental data from animals or humans.

Next, scientists should adopt Good Modelling Practices and a step-by-step approach when developing PBK models to ensure transparency.

Benchmark datasets and standardised metrics need to be developed to evaluate quantitative in vitro to in vivo extrapolation predictions.

Finally, case studies should be developed to increase regulators’ confidence in generic PBK model predictions, as well as providing critical inputs for developing guidelines.

The full report of the ECETOC workshop’s findings has been published in the scientific journal Archives of Toxicology and can be found at https://doi.org/10.1007/s00204-022-03356-5.