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New guidance for using computational models in chemical risk assessment

OECD Guidance document on the characterisation, validation and reporting Physiologically Based Kinetic models for regulatory purposes
Apr 13 2021

JRC researchers have led the development of international guidance to support the use of physiologically based kinetic models in chemical risk assessment. The guidance document has been adopted and published by the Organisation for Economic Co-operation and Development (OECD).

Physiologically based kinetic (PBK) models are playing an increasingly important role in chemical risk assessment. These models simulate what the body does to the chemical, in terms of how the chemical is absorbed, distributed, metabolised and eliminated.

The human health risks of a chemical are directly linked to its levels in body tissues, which vary over time as the chemical is absorbed and removed.

The JRC led the OECD project on behalf of the European Commission and in collaboration with the US Environmental Protection Agency, following up on recommendations from a JRC workshop held in 2016.

Uses of physiologically based kinetic models

In a modern toxicological framework, PBK models are used alongside in vitro methods that characterise the hazardous properties of chemicals. By allowing extrapolation from in vitro data, this next generation of PBK models provides a means of conducting chemical risk assessments more efficiently and reliably, without testing on animals to measure tissue levels of chemicals.

PBK models can be used to better understand the effects not only of single chemicals, but also chemical mixtures. They can also be used to better interpret human biomonitoring data, where this information is available, for example from the JRC’s Information Platform for Chemical Monitoring (IPCHEM). 

The challenges

Even though PBK modelling technology is now mature, and has been used in other sectors (notably pharmaceuticals) for decades, the uptake of PBK models in the regulatory assessment of chemicals has been slow.

“The next generation of PBK models has introduced some unfamiliar uncertainties into the risk assessment process and this is impeding their acceptance and use”, comments JRC scientist Alicia Paini. “The guidance document we've developed with OECD partners helps build confidence by providing a framework for assessing and reporting the characteristics of these models in a way safety assessors can understand.”

A particular challenge with these new models concerns model validation. According to JRC scientist Andrew Worth, "often there is no information on the level or concentration of chemicals taken up in body tissues following exposure. This means that there is no benchmark for comparing the simulated tissue concentrations with real-life data. However, in some situations there's a work-around, as we explain in the guidance.”

Key features

The document builds on existing international guidance for PBK models, while emphasising aspects relevant for a next generation of models. Key features of the guidance include:

  • how to deal with PBK models built using data from non-animal methods (in vitro and in silico);
  • how to establish model validity, including in situations where in vivo data are lacking (the “read-across approach” to model validation);
  • a template for reporting the characteristics of PBK models;
  • a checklist to ensure the completeness of documentation on PBK models;
  • a series of case studies to illustrate the practical application of the guidance. 

These features are summarised in a recent commentary by the project leaders. A further publication illustrates the read-across approach to model validation in cases where in vivo data are lacking.

Find out more

Watch a dedicated webinar hosted by the OECD on 10 May, 13:20 - 15:30 CEST.