Toxicokinetics Reveal Structure-Related Differences in Developmental Toxicity among Typical Aromatic Disinfection Byproducts in Zebrafish Embryos

Aromatic disinfection byproducts (DBPs) are emerging contaminants generated during drinking water disinfection and exhibit higher cytotoxicity and genotoxicity than traditional aliphatic DBPs. However, in vivo toxicokinetic behavior of aromatic DBPs during sensitive developmental stages remains poorly understood, limiting accurate risk assessment. Here, five aromatic DBPs within three classes (halophenols, halonitrophenol, and halohydroxybenzaldehydes) were systematically investigated using zebrafish embryos to compare developmental toxicity and characterize toxicokinetics. Developmental toxicity tests showed that the median lethal concentrations (LC50) of halonitrophenol were lower than halophenols and halohydroxybenzaldehydes, and brominated analogues were consistently more toxic than chlorinated counterparts. When expressed as median lethal residues (LR50) instead of LC50, toxicity differences decreased from 13-fold to 3-fold, indicating that reliance on external concentrations may misrepresent toxic potency. Toxicokinetic analysis showed that halophenol and halonitrophenol DBPs exhibited higher uptake and slower elimination, resulting in appreciable bioaccumulation and elevated internal exposure. In contrast, halohydroxybenzaldehydes exhibited substantially lower uptake rate constants, whereas elimination rate constants were 2-3 orders of magnitude higher, collectively resulting in extremely low bioaccumulation and negligible internal residues. These distinct kinetic profiles provide, for the first time among aromatic DBPs, insights linking chemical structure, internal exposure, and toxicity, supporting more biologically relevant risk-based prioritization.