Polybrominated and chlorinated dibenzo-p-dioxins: synthesis biologic and toxic effects and structure-activity relationships

A series of polybrominated dibenzo-p-dioxins (PBDDs) and 2,3,7,8-substituted polybrominated and chlorinated analogs were synthesized and their relative in vivo and in vitro activities were determined. The structure-activity relationships (SARs) for PBDDs as ligands for the 2,3,7,8-TCDD cytosolic receptor were comparable to those observed for the polychlorinated dibenzo-p-dioxins (PCDDs); the most active compounds were substituted in all four lateral positions and there was a decrease in binding affinities with a decrease in lateral substituents or an increase in non-lateral substituents. The binding affinities of 2,3,7,8-tetrachloro, 2-bromo-3,7,8-dichloro-, 2,3-dibromo-7,8-dichloro-, 2,8-dibromo-3,7-dichloro and 2,3,7,8-tetrabromodibenzo-p-dioxin were comparable using the hydroxylapatite assay and indicates that interchange of Br and Cl substituents does not significantly alter binding affinities. The in vivo effects (monooxygenase enzyme induction, thymic atrophy and body weight loss) of several PBDDs were also determined in the immature male Wistar rat. 2,3,7,8-Tetrabromodibenzo-p-dioxin was the most toxic compound in this series and exhibited a toxic potency comparable to that of 2,3,7,8-TCDD. The relative toxic potencies of the PBDDs used in this study followed the order 2,3,7,8- > 1,2,3,7,8- > 1,2,4,7,8- > 1,3,7,8- and a comparable rank order was previously observed with the corresponding PCDD isostereomers.