The transition to a pathway-based approach to risk assessment will require significant investment in the development of exposure science. Current approaches such as estimation of external applied dose and application of exposure-based waiving will continue, however higher tier exposure tools will be required to better understand the bioavailability of chemicals in the human body. Investment is therefore required into scientifically more advanced and toxicologically relevant approaches that permit the estimation of internal dose in humans.
Physiologically-based biokinetic (PBBK) modelling is recognised as the means to achieve this, simulating whole-body toxicokinetic profiles by integrating chemical-independent (physiological) and chemical-dependent (absorption, deposition, metabolism and excretion, (ADME)) parameters. The predicted internal plasma and/or tissue concentration (e.g. in µM) can then be compared to concentration-response curves generated in vitro for the purposes of risk assessment.

The growing emphasis on the utilisation of in vitro systems raises a key challenge in the need for improved tools to model, measure and control the free concentration of chemicals in selected in vitro systems of interest. Current practice typically relates results obtained from an in vitro test system to a nominal concentration, which acts as a surrogate in establishing dose-response relationships. However, depending on the physicochemical properties of a chemical variability between the nominal and freely dissolved concentration may exist due to binding to serum constituents, plastic and/or cells. The development of tools for modelling, measuring and controlling free concentration in in vitro test systems is required to facilitate the improved prediction of in vivo parameters on the basis of in vitro studies, termed quantitative in vitro in vivo extrapolation (QIVIVE).

Research activities aligned with the development of approaches for estimation of internal dose include the evaluation of PBBK models for the dermal route of exposure and the development of an improved understanding of the uncertainty associated with the model output.
In the area of improved approaches to facilitate QIVIVE we are collaborating with the Institute for Risk Assessment Science at Utrecht University. We are systematically investigating how physicochemical properties of the chemical, in combination with the specific conditions of the in vitro assay of interest, determine the free concentration in the test system. Together with the Waterloo University we are developing approaches for the non-depletive measurement of free concentration time profiles in multi-well in vitro assays.

Latest Presentation

Dose Metric Considerations in In Vitro Assays
Bovine Serum Albumin and Plastic Binding: Impact on Toxicity of Cationic Chemicals in In Vitro Cell Assays

Latest Publication

Coming soon

Dr. Claire Davies