Studying interaction effects on toxicokinetics in zebrafish combining experimental and modelling approaches

Area of Science:

• Environmental Chemistry
• Toxicology
• Zebrafish Models

Background:

• Chemical risk assessments often evaluate single substances, neglecting complex mixture interactions.
• Understanding toxicokinetic and toxicodynamic mixture effects is crucial for accurate risk assessment.
• Anthropogenic chemical mixtures pose risks to humans and wildlife, with limited regulatory oversight.

Purpose of the Study:

• To investigate interaction effects on absorption, distribution, metabolism, and excretion (ADME) processes of selected anthropogenic chemicals.
• To determine bioconcentration factors (BCFs) for nine chemicals in zebrafish exposed to a mixture.
• To develop and utilize physiologically based kinetic (PBK) models to simulate mixture effects.

Main Methods:

• Adult female zebrafish (Danio rerio) were exposed to a mixture of 11 chemicals.
• Bioconcentration factors (BCFs) were determined for nine chemicals.
• Physiologically based kinetic (PBK) models were developed and applied for bisphenols and per- and polyfluoroalkyl substances (PFAS).

Main Results:

• No statistically significant differences in BCFs for bisphenols were observed between single and mixture exposures.
• PBK models showed good fit for bisphenol A (BPA), bisphenol Z (BPZ), bisphenol AF (BPAF), and perfluorooctanesulfonic acid (PFOS).
• Simulations indicated that high levels of PFOS (>1 μg/L) could alter bisphenol tissue levels through competitive protein binding.

Conclusions:

• Mixture effects on bisphenol kinetics were not significant at the investigated concentrations.
• Chemicals can perturb ADME processes in concert, but primarily at higher concentrations or within complex mixtures.
• PBK modeling is a valuable tool for predicting kinetic interactions in chemical mixtures.