Lack of Synergy by Mixtures of Weakly Estrogenic Hydroxylated Polychlorinated Biphenyls and Pesticides

Abstract

We examined the estrogenicity of binary mixtures of the hydroxylated polychlorinated biphenyls (OHPCBs) 2,4,6-trichloro-4'-biphenylol (2,4,6-TCB-4'-OH) and 2,3,4,5,-tetrachloro-4'-biphenylol and the pesticides endosulfan and dieldrin. The OHPCBs and pesticides were tested in both the MCF-7 focus assay and a competitive estrogen-receptor binding assay. Although the individual OHPCBs were estrogenic in both assays, there was no synergy when they were combined at various concentrations as equimolar mixtures. Of the pesticides, only endosulfan was estrogenic. Its weak estrogenicity was seen only in the MCF-7 focus assay at the highest concentration tested-10 pM. There was no synergy of the equimolar mixture of pesticides. To determine whether OHPCBs might respond synergistically when combined with the natural estrogen 17-estradiol (E2), we tested various concentrations of 2,4,6-TCB-4'-OH in the MCF-7 focus assay in combination with physiologically relevant concentrations of E2. There was no synergy between 2,4,6-TCB-4'-OH and E2. Pretreatment for 3 or 7 days with 2,4,6-TCB-4'-OH had no effect on subsequent foci induced by a combination of 2,4,6-TCB-4'-OH and E2. Although our results showing no synergy between the pesticides or the OHPCBs are in contrast to a recent report that binary mixtures of these same compounds produce synergistic responses in estrogen-sensitive assays, they are in agreement with the results from other assays showing a lack of synergy. Considering all results, it appears that synergy of these weakly estrogenic compounds acting through the estrogen receptor is unlikely.

Polychlorinated Biphenyls and Polybrominated Biphenyls

“…Although the individual OH-PCBs were estrogenic in both assays, there was no synergy when they were combined at various concentrations as equimolar mixtures (Arcaro et al, 1998). Likewise, the estrogenic activities of these two OH-PCBs were additive when tested as equimolar mixture in several systems (MCF-7 cells, MDA-MB-231 human breast-cancer cells, mouse uterus) at high and low levels of estrogen-receptor expression, confirming the lack of a synergistic effect .…”

Human health and chemical mixtures: an overview.

“…Figure 11 shows Log molarity of E2 -8 Figure 11. The estrogenic effects of three concentrations of 2,4,6-trichloro-4'-biphenylol alone and together with dose-response curves of E2 in the MCF-7 cell focus assay, as described by Arcaro et al (42). The data show no synergistic effect when the biphenylol at various concentrations was added together with E2.…”

“…On the basis of this assumption, some have concluded that the PCBs that cannot assume a coplanar configuration are nontoxic (31), but this has now been proven incorrect. Results from our laboratories and those of a number of other researchers (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) (32) showed that congeners with two or more ortho chlorines inhibit the enzyme tyrosine hydroxylase, which is the rate-limiting enzyme for the synthesis of the neurotransmitter dopamine. Kodavanti et al (33) and Carpenter et al (34) showed that orthosubstituted, but not coplanar, congeners kill cerebellar granule cells by a mechanism that probably involves disruption of calcium homeostasis.…”

Structure-activity relationships and pathway analysis of biological degradation processes

“…1) also contain EDC activity. 15,16) A few of the numerous QSAR models available to describe EDC activity are discussed below to illustrate the breadth of available methodologies and applications.…”