Abstract
The toxic equivalency concept used for the risk assessment of polychlorinated biphenyls (PCBs) is based on the aryl hydrocarbon receptor (AhR)-mediated toxicity of coplanar dioxin-like (DL) PCBs. Most PCBs in the environment, however, are non-dioxin-like (NDL) PCBs that cannot adopt a coplanar structure required for AhR activation. For NDL-PCBs, no generally accepted risk concept is available because their toxicity is insufficiently characterized. Here, we systematically determined in vitro toxicity profiles for 24 PCBs regarding 10 different mechanisms of action. Prior to testing, NDL-PCB standards were purified to remove traces of DL compounds. All NDL-PCBs antagonized androgen receptor activation and inhibited gap junctional intercellular communication (GJIC). Lower chlorinated NDL-PCBs were weak estrogen receptor (ER) agonists, whereas higher chlorinated NDL-PCBs were weak ER antagonists. Several NDL-PCBs inhibited estradiol-sulfotransferase activity and bound to transthyretin (TTR) but with much weaker potencies than reported for hydroxylated PCB metabolites. AhR-mediated expression of uridine-glucuronyl transferase isozyme UGT1A6 was induced by DL-PCBs only. Hierarchical cluster analysis of the toxicity profiles yielded three separate clusters of NDL-PCBs and a fourth cluster of reference DL-PCBs. Due to small differences in relative potency among congeners, the highly abundant indicator PCBs 28, 52, 101, 118, 138, 153, and 180 also contributed most to the antiandrogenic, (anti)estrogenic, antithyroidal, tumor-promoting, and neurotoxic potencies calculated for PCB mixtures reported in human samples, whereas the most potent AhR-activating DL-PCB-126 contributed at maximum 0.2% to any of these calculated potencies. PCB-168 is recommended as an additional indicator congener, given its relatively high abundance and antiandrogenic, TTR-binding, and GJIC-inhibiting potencies.
Highlights
Polychlorinated biphenyls (PCBs) are synthetic organic compounds, with high resistance against electrical, thermal, chemical, or biological breakdown
No risk assessment model similar to the toxic equivalency (TEQ) concept is available for NDL-PCBs, various adverse effects on thyroid, liver, brain, immune system, estrous cycling, reproduction, and neurodevelopment have been reported for animal studies with individual NDL-PCB congeners (EFSA, 2005)
Most PCBs had higher androgen receptor (AR)-antagonistic potency than the reference compound flutamide, an antiandrogenic drug used in prostate cancer treatment, whereas their potencies were in the same order of magnitude as those reported for polybrominated diphenyl ethers (PBDEs) PBDE-100 and PBDE-47 (IC50 1⁄4 0.1 and 1.0lM, respectively), which are the strongest AR antagonists with environmental relevance reported to date (Hamers et al, 2006)
Summary
Polychlorinated biphenyls (PCBs) are synthetic organic compounds, with high resistance against electrical, thermal, chemical, or biological breakdown. Despite the ban on their production, PCBs remain to be an environmental problem due to their high persistency and ongoing ‘‘leaking’’ to the environment from existing applications and waste Based on their toxicological mechanism of action, PCB congeners can be divided into two groups. In order to improve the hazard characterization of NDLPCBs, the aims of the present systematic in vitro screening study were (1) to screen the toxic potency of structurally representative and highly purified NDL-PCBs to identify relevant mechanisms of action for NDL-PCBs in man and wildlife, (2) to classify NDL-PCBs into clusters with similar toxicity profiles, and (3) to determine the relative importance of individual NDL-PCB congeners to the calculated toxic potency of a complex mixture of PCBs present in human samples (blood and adipose tissue). The complete test set of PCBs including their substitution pattern, molecular weight, and structural formula is given in Supplementary figure 1
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