Toxicokinetic Modeling of Per- and Polyfluoroalkyl Substance Concentrations within Developing Zebrafish (Danio rerio) Populations

Abstract

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental contaminants, and their relative stability and high bioaccumulation potential create a challenging risk assessment problem. Zebrafish (Danio rerio) data, in principle, can be synthesized within a quantitative adverse outcome pathway (qAOP) framework to link molecular activity with individual or population level hazards. However, even as qAOP models are still in their infancy, there is a need to link internal dose and toxicity endpoints in a more rigorous way to further not only qAOP models but adverse outcome pathway frameworks in general. We address this problem by suggesting refinements to the current state of toxicokinetic modeling for the early development zebrafish exposed to PFAS up to 120 h post-fertilization. Our approach describes two key physiological transformation phenomena of the developing zebrafish: dynamic volume of an individual and dynamic hatching of a population. We then explore two different modeling strategies to describe the mass transfer, with one strategy relying on classical kinetic rates and the other incorporating mechanisms of membrane transport and adsorption/binding potential. Moving forward, we discuss the challenges of extending this model in both timeframe and chemical class, in conjunction with providing a conceptual framework for its integration with ongoing qAOP modeling efforts.

Keywords: PFAS; adsorption; binding; bioaccumulation; diffusion; membrane transporters; toxicokinetics; zebrafish embryo.

Figure 1

Parity plot presentation of the transporter model predictions against that of both the Vogs model data and other data available in the literature^,,− (incorporating both pre- and post-hatching phases) for the chorion/embryo system in the concentration domain. When necessary, data were converted to a mass/zebrafish basis before being converted to a concentration basis using our proposed volume model. We assumed a wet weight of 500 μg^, for the Han et al. conversion. The shaded region indicates an area bounded by a factor of 2 from unity, and the standard deviation lines of the data from unity are included.

Figure 2

Transporter model results for embryo PFAS net uptake (flux) compared against that of the Vogs model. Fluxes from the Vogs model were estimated by multiplying their change in the concentration and volume predictions.

Figure 3

Transporter model results compared against that of the Vogs model for chorion/embryo system mass after extrapolating all models past 5 dpf to 10 dpf for three different exposure concentrations.

Figure 4

Chorion/embryo system PFAS mass expressed over a range of exposure concentrations and times predicted using our transporter model (curves). Vogs model data are shown with symbols.

Figure 5

Our transporter model predicts some nonmonotonic AF profiles that evolve over time (curves), illustrated here for several different constant exposure concentrations. Here, we calculate AF as the ratio of the chorion/embryo system concentration to that of the constant exposure concentration. AF data (open symbols) reported or derived from the literature^,,− are also shown with a similar calculation strategy as with Figure 1. Closed symbols (as depicted in the legend) represent our model predictions for those same data points, whereby giving a sense for the magnitude of the literature exposure concentrations and our model’s fidelity with the literature in the AF domain.