JRC researchers develop a predictive tool for assessing human bioaccumulative potential
|Dec 02, 2011|
|Contact: JRC-IHCP, Computational Toxicology and Modelling|
|A. Tonnelier, S. Coecke and José-M. Zaldívar|
Due to the high number of synthetic chemicals, there is a need to develop prioritisation strategies, identifying which of these chemicals are of most concern. In these risk assessment strategies, bioaccumulation is always an important element. However current bioaccumulation criteria, developed for aquatic organisms, fail to identify substances that are bioaccumulative for terrestrial ecosystems, including humans.
The purpose of this study was to develop a predictive tool for human bioaccumulation assessment that incorporates not only the chemical properties of the compounds, but also the processes that tend to decrease the concentration of the compound, such as metabolisation and excretion.
The authors, researchers at the Joint Research Centre, Institute for Health and Consumer Protection (JRC-IHCP), used a generic physiologically-based toxicokinetic (PBTK) model based on in vitro human liver metabolism data, minimal renal excretion and a constant exposure, that was able to assess the bioaccumulative potential of a chemical. According to this model, a generalised boundary diagram that provides a fast assessment for human bioaccumulation potential was developed (see figure). Thus, human bioaccumulation can be assessed with only two in vitro tests: one aimed at calculating the chemical binding to plasma proteins, and the other at estimating the liver clearance by in vitro measuring the metabolite formation and/or the substrate depletion of the compound using human hepatocytes.
The results provide further evidence that partitioning properties do not allow for reliable screening criteria for human bioaccumulation.
The approach has been analysed using literature data on well-known bioaccumulative compounds (PCBs, DDT, PFOS), liver metabolism data from the European Center for Validation of Alternative Methods (ECVAM) database and a subset of the ToxCast phase I chemical library - in total 94 compounds covering pharmaceuticals, plant protection products and industrial chemicals.
The assumptions in this modelling approach are conservative and, therefore, it is more probable to obtain false positives (compounds appearing to bioaccumulate, while in fact they are not) than false negatives (compounds appearing not to bioaccumulate, while in fact they are) as it was observed for some compounds that deviate in the comparison between experimental data and predictions.
Arnaud Tonnelier, Sandra Coecke and José-Manuel Zaldívar. Screening of chemicals for human bioaccumulative potential with a physiologically based toxicokinetic model (PBTK), Archives of Toxicology, Springer Berlin, Heidelberg, December 2011, doi: 10.1007/s00204-011-0768-0
Figure: Boundary diagram for human bioaccumulation assessment based on liver clearance and plasma unbound fraction.
Photo: Scientists at work in the JRC-IHCP Computational Toxicology laboratory. Copyright European Union 2010.