Toxicity and risk priority ranking of polybrominated diphenyl ethers (PBDEs): A relative receptor-bound concentration approach

Abstract

Toxicity and risk priority ranking of chemicals are crucial to management and decision-making. In this work, we develop a new mechanistic ranking approach of toxicity and risk priority ranking for polybrominated diphenyl ethers (PBDEs) based on receptor-bound concentration (RBC). Based on the binding affinity constant predicted using molecular docking, internal concentration converted from human biomonitoring data via PBPK model, and the receptor concentration derived from the national center for biotechnology information (NCBI) database, the RBC of 49 PBDEs binding to 24 nuclear receptors were calculated. 1176 RBC results were successfully obtained and analyzed. High brominated PBDEs, including BDE-201, BDE-205, BDE-203, BDE-196, BDE-183, BDE-206, BDE-207, BDE-153, BDE-208, BDE-204, BDE-197, and BDE-209, exerted more potent than low brominated congeners (BDE-028, BDE-047, BDE-099, and BDE-100) at the same daily intake dose in terms of toxicity ranking. For risk ranking, with human biomonitoring serum data, the relative RBC of BDE-209 was significantly greater than that of any others. For receptor prioritization, constitutive androstane receptor (CAR), retinoid X receptor alpha (RXRA), and liver X receptor alpha (LXRA) may be the sensitive targets for PBDEs to trigger effects in the liver. In summary, high brominated PBDEs are more potent than low brominated congeners, thus, besides BDE-047 and BDE-099, BDE-209 should be priority controlled. In conclusion, this study provides a new approach for toxicity and risk ranking of groups of chemicals, which can readily be used for others.

Keywords: Molecular docking; Physiologically based pharmacokinetic (PBPK) modeling; Polybrominated diphenyl ethers (PBDEs); Receptor-bound concentration (RBC); Toxicity and risk ranking.