Assessment of synergistic thyroid disrupting effects of a mixture of EDCs in ovariectomized rats using factorial analysis and dose addition

Abstract

Endocrine disrupting chemicals (EDCs) have been implicated in a broad spectrum of health problems related to reproduction, thyroid function, neurodevelopment, and metabolism. In many cases, EDCs in the environment are at extremely low concentrations which rarely induce health problems alone, however, a mixture of these EDCs may interact and induce potential additive and synergistic effects. Many mixture studies on EDCs were conducted in terms of high doses with the direct effect addition method, which didn't comply with the dose–response relationship of toxicants in the “S” or “U” shaped curves. In the present study, the thyroid disrupting effects of a mixture of three EDCs, propylthiouracil (PTU), polychlorinated biphenyls (PCBs), and ammonium perchlorate (AP), were measured in an ovariectomized rat model. Sixty female SD rats were ovariectomized bilaterally and randomly assigned to ovariectomization (OVX) control, PTU + PCBs, PTU + AP, PCBs + AP and PTU + PCBs + AP groups treated with doses at lowest observed adverse effect levels (LOAELs) or benchmark dose lower limits (BMDLs) obtained from our previous dose–response relationship studies. OVX control animals were treated with vehicle control while all other animals were treated with different combinations of EDCs by gavage for 8 days. The body weight change, serum total thyroxine (tT₄), triiodothyroxine (tT₃), the thyroid/body weight ratio, and thyroid histopathological endpoints were measured and analyzed using factorial analysis and dose addition. All EDC treated groups showed a marked change compared to vehicle control in serum tT₄, the thyroid/body weight ratio, and the thyroid epithelium/colloid ratio. Both factorial analysis and dose addition analysis showed a synergistic effect on thyroid function by PTU, PCBs and AP together, but the modes of interaction varied when either two were mixed at LOAELs. To conclude, a mixture of PTU, PCBs, and AP mainly acted synergistically on thyroid function and induced a significant health effect.