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

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.