| Interactive Effects of Environmentally Relevant Polychlorinated Biphenyls and Dioxins on [3H]Phorbol Ester Binding in Rat Cerebellar Granule Cells Prasada Rao S. Kodavanti and Thomas R. Ward Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA Abstract
Polychlorinated biphenyls (PCBs) are persistent contaminants that exist as complex mixtures in the environment. One problem faced by risk assessors is that the possible interactive effects of specific PCB congeners and related chemicals found in environmental and biological samples have not been systematically investigated. Some PCBs perturb Ca2+ homeostasis and cause protein kinase C (PKC) translocation in neuronal cell cultures and in brain homogenate preparations at concentrations where no cytotoxicity is observed, and these systems are necessary for the growth and normal functioning of neurons. The changes in second messenger systems appear to be associated with the extent of noncoplanarity of the PCB molecule. We studied the interactive effects of selected PCB congeners, a PCB metabolite, and a dioxin on PKC translocation, as determined by [3H]phorbol ester binding in cerebellar granule cells. The binary combinations included coplanar and noncoplanar PCB congeners or PCB congeners with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) /PCB metabolite. In addition, we tested the interactive effects of several 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 activity of the noncoplanar (2,2´,5,5´-TeCB) or coplanar [4,4´-dichlorobiphenyl (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 mixtures at the ratios found in environmental samples are biologically active ; and 6) there was no indication of synergism in any of the combinations 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 mixtures contain mostly noncoplanar PCB congeners, and because they appear to be biologically active, the potential human health risk by this group of chemicals should be considered in the risk assessment of PCBs. Key words: binary combinations, cerebellar granule cells, environmental mixtures, interactive effects, neurotoxicity, [3H]phorbol ester binding, polychlorinated biphenyls, polychlorinated dibenzodioxins. Environ Health Perspect 106:479-486 (1998) . [Online 8 July 1998] http://ehpnet1.niehs.nih.gov/docs/1998/106p479-486kodavanti/ abstract.html Address correspondence to P.R.S. Kodavanti, Neurotoxicology Division, MD 74B, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. We thank Ethel Derr-Yellin for maintaining cell cultures, protein analysis, and excellent technical assistance ; Theresa Freudenrich for maintaining cell cultures ; and Hugh Tilson and Kevin Crofton for helpful discussions. Michael Santostefano and Angelique van Birgelen are acknowledged for their critical review of an earlier version of the manuscript. Preliminary findings were presented at the Annual Meeting of Experimental Biology, Washington, DC, 14-17 April 1996. The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Received 25 November 1997 ; accepted 25 March 1998.
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