INTERACTIVE EFFECTS OF ENVIRONMENTALLY RELEVANT POLYCHLORINATED-BIPHENYLS AND DIOXINS ON [H-3]PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLS

polychlorinated biphenyls (PCBs) are persistent contaminants that exis t as complex mixtures in the environment. One problem faced by risk as sessors is that the possible interactive effects of specific PCB conge ners and related chemicals found in environmental and biological sampl es have not been systematically investigated. Some PCBs perturb Ca2+ h omeostasis and cause protein kinase C (PKC) translocation in neuronal fell cultures and in brain homogenate preparations at concentrations w here no cytotoxicity is observed, and these systems are necessary for the growth and normal functioning of neurons. The changes in second me ssenger systems appear to be associated with the extent of noncoplanar ity of the PCB molecule. We studied the interactive effects of selecte d PCB congeners, a PCB metabolite, and a dioxin on PKC translocation, as determined by [H-3]phorbol ester binding in cerebellar granule cell s. The binary combinations included coplanar and noncoplanar PCB conge ners or PCB congeners with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/ PCB metabolite. In addition, we tested the interactive effects of seve ral PCB congeners (three or more) found in environmental samples such as human milk and blood, contaminated fish, and brain samples from PCB -treated animals. The results indicated that 1) the coplanar congener [3,3',4,4'-tetrachlorobiphenyl (TeCB)] did not alter the in vitro acti vity of the noncoplanar (2,2',5,5'-TeCB) or coplanar [4,4'-dichlorobip henyl (DCB)] congeners; 2) binary mixtures of active PCB congeners (2, 2',4,4'-TeCB and 2,2'-DCB; 2,2'-DCB and 3,5-DCB; 2,2',3,5',6-PeCB and 2,2',4,4',5-PeCB) interact in a dose-additive manner; 3) TCDD did not alter the activity of either coplanar (3,3',4,4'-TeCB) or noncoplanar (2,2',5,5'-TeCB) congeners; 4) the interaction between the parent PCB congener and hydroxy metabolite of PCB is additive; 5) PCB congener mi xtures at the ratios found in environmental samples are biologically a ctive; and 6) there was no indication of synergism in any of the combi nations studied. These results suggest that the biological effects of binary mixtures of PCB congeners fit a dose-additive model, indicating that there is a specific site of action for these PCB congeners which is independent of the aryl hydrocarbon receptor. Environmental mixtur es contain mostly noncoplanar PCB congeners, and because they appear t o be biologically active, the potential human health risk by this grou p of chemicals should be considered in the risk assessment of PCBs.