Differential Toxicokinetics and Bioconcentration of Cationic and Anionic Organic Compounds during Zebrafish ( Danio rerio ) Development

Ionizable organic compounds (IOCs) represent an important class of environmental chemicals. Though zebrafish embryos are increasingly utilized as alternative vertebrate models in chemical hazard and risk assessment related to human health and the environment, it remains unclear whether life-stage-specific physiology alters toxicokinetics and bioconcentration potential of IOCs. Here, we examined toxicokinetics and bioconcentration factors (BCFs) of eight ionizable pharmaceuticals with diverse physicochemical properties using a mixture exposure design across embryonic and larval stages of zebrafish. Coexposure did not markedly alter toxicokinetic parameters for the IOCs relative to single exposure at similar concentrations. We observed development-dependent and ionization-state-specific toxicokinetic processes and accumulation in zebrafish. Larvae exhibited an enhanced uptake and reduced elimination for cationic compounds. Importantly, the BCF values of cationic amitriptyline and cisapride exceeded the regulatory bioaccumulation threshold in larvae. Conversely, most anionic compounds displayed lower uptake and elimination in larvae, yielding similar BCFs across the stages. Further, we identified higher bioaccumulation for cations than anions in larvae, and IOC bioconcentration was generally elevated in larvae compared with embryos, which is increasingly employed in basic and translational environmental and biomedical studies. These findings highlight the importance of considering life stage and ionization state when using zebrafish as alternative models in risk assessment.