A mixture of persistent organic pollutants relevant for human exposure inhibits the transactivation activity of the aryl hydrocarbon receptor in vitro

While humans are exposed to mixtures of persistent organic pollutants (POPs), their risk assessment isusually based on a chemical-by-chemical approach. To assess the health effects associated with mixedexposures, knowledge on mixture toxicity is required. Several POPs are potential ligands of the Arylhydrocarbon receptor (AhR), which involves in xenobiotic metabolism and controls many biologicalpathways. This study assesses AhR agonistic and antagonistic activities of 29 POPs individually and inmixtures by using Chemical-Activated LUciferase gene eXpression bioassays with 3 transgenic cell lines(rat hepatoma DR-H4IIE, human hepatoma DR-Hep G2 and human mammary gland carcinoma DR-T47-D). Among the 29 POPs, which were selected based on their abundance in Scandinavian human blood,only 4 exerted AhR agonistic activities, while 16 were AhR antagonists in DR-H4IIE, 5 in DR-Hep G2 and 7in DR-T47-D when tested individually. The total POP mixture revealed to be AhR antagonistic. Itantagonized EC50TCDD inducing AhR transactivation at a concentration of 125 and 250 and 500 foldblood levels in DR-H4IIE, DR-T47-D and DR-Hep G2, respectively, although each compound was presentat these concentrations lower than their LOEC values. Such values could occur in real-life in foodcontamination incidents or in exposed populations. In DR-H4IIE, the antagonism of the total POP mixturewas due to chlorinated compounds and, in particular, to PCB-118 and PCB-138 which caused 90% of theantagonistic activity in the POP mixture. The 16 active AhR antagonists acted additively. Their mixedeffect was predicted successfully by concentration addition or generalized concentration additionmodels, rather than independent action, with only two-fold IC50underestimation. We also attained goodpredictions for the full dose-response curve of the antagonistic activity of the total POP mixture