Can TK-TD modelling bridge the gap between in vitro and in vivo mammalian toxicity data?

Abstract

Repeated dietary dose testing is used to assess longer term toxicity of chemicals, such as pesticides, to mammals. However, the internal pesticide concentration varies significantly as feeding rate relative to body size fluctuates over time. Toxicokinetic-toxicodynamic (TK-TD) models can estimate internal toxicant concentration over time and link this directly to observed effects on endpoints such as the growth rate of laboratory rats. Using TK-TD models it is therefore possible to predict the effects that would result from a constant internal concentration of a pesticide. This presents the possibility of comparison with data from in vitro experiments, potentially facilitating quantitative in vitro to in vivo extrapolation (QIVIVE). We used in vivo TK-TD models to identify relevant internal concentrations and then estimated the experimental conditions required to replicate these in cultured cells, using in vitro TK models. Cell population growth was measured, with a view to extrapolating through time and comparing effect sizes with in vivo predictions. However, observed cell proliferation was not significantly affected by the tested concentrations of any of the five pesticides in this study and so extrapolation was not possible. In light of this negative result, we highlight areas for future work towards QIVIVE of graded sublethal effects in mammals. The most pressing objective is improving the accuracy of in vivo TK predictions, which could be achieved with dietary dosing in TK studies.