Development of a Web-Based Toolbox to Support Quantitative In-Vitro-to-In-Vivo Extrapolations (QIVIVE) within Nonanimal Testing Strategies

The goal of the present study was
to develop an online web-based
toolbox that contains generic physiologically based kinetic (PBK)
models for rats and humans, including underlying calculation tools
to predict plasma protein binding and tissue:plasma distribution,
to be used for quantitative in-vitro-to-in-vivo extrapolations (QIVIVE).
The PBK models within the toolbox allow first estimations of internal
plasma and tissue concentrations of chemicals to be made, based on
the logP and pKa of the chemicals and
values for intestinal uptake and intrinsic hepatic clearance. As a
case study, the toolbox was used to predict oral equivalent doses
of in vitro ToxCast bioactivity data for the food additives methylparaben,
propyl gallate, octyl gallate, and dodecyl gallate. These oral equivalent
doses were subsequently compared with human exposure estimates, as
a low tier assessment allowing prioritization for further assessment.
The results revealed that daily intake levels of especially propyl
gallate can lead to internal plasma concentrations that are close
to in vitro biological effect concentrations, particularly with respect
to the inhibition of human thyroid peroxidase (TPO). Estrogenic effects
were not considered likely to be induced by the food additives, as
daily exposure levels of the different compounds remained 2 orders
of magnitude below the oral equivalent doses for in vitro estrogen
receptor activation. Overall, the results of the study show how the
toolbox, which is freely accessible through www.qivivetools.wur.nl,
can be used to obtain initial internal dose estimates of chemicals
and to prioritize chemicals for further assessment, based on the comparison
of oral equivalent doses of in vitro biological activity data with
human exposure levels.