Unraveling the Mechanisms and Drivers of Brominated Flame Retardant Toxicity in Aquatic Animals

The global phase-out of legacy brominated flame retardants (BFRs) has coincided with the increasing detection of novel BFRs in the environment, creating a complex scenario of coexisting legacy and novel pollutants. Aquatic systems serve as major sinks for BFRs, making it imperative to assess the potential ecological risks posed by BFRs to aquatic animals. This study synthesized 8009 valid data points from 137 publications using meta-analysis, machine learning, and the Geodetector model. Meta-analysis revealed that biological factors (life stage and ecological niche) are important determinants of species sensitivity to BFRs, with early life stages, adults and benthic animals exhibiting stronger responses. Exposure conditions (BFR type, exposure time and concentration) were also important factors driving toxicity, particularly the significant effects induced by banned BFRs, high concentration exposure (> 1000 μg/L) and chronic exposure (> 14 days). A non-monotonic dose-response relationship was observed, indicating that the toxic effects did not follow a simple linear concentration‑dependent pattern. Toxicological endpoint analysis identified cytotoxicity and endocrine disruption as dominant effects. Machine learning and Geodetector model identified endpoint and BFR type as the most important factors, with widespread interactive enhancement effects among the factors. Notably, decabromodiphenyl ethane (DBDPE), a primary alternative to decabromodiphenyl ether (BDE-209), exhibited effect magnitudes comparable to or even greater than those of BDE‑209 for certain endpoints (e.g., programmed cell death and thyroid endocrine). Its toxicity was also more susceptible to modulation by exposure conditions. These findings challenge the perceived safety of DBDPE as a "safer alternative" and underscore its non‑negligible ecological risk. Mechanistically, comparative analysis of ecological niches across species indicated that the same BFR could trigger divergent adverse outcome pathways in different species, attributable to species-specific molecular initiating events.