We compared the effects of two polychlorinated biphenyls (PCB) congeners on Ca(2+) homeostasis in cerebellar granule cells: 2,2'-dichlorobiphenyl (DCBP), a putative neurotoxic congener, and 3,3',4,4',5-pentachlorobiphenyl (PCBP), a presumed nonneurotoxic congener. In cerebellar granule cells (6-8 days in vitro), DCBP was cytotoxic as indicated by a significant increase in LDH leakage at 200 microMols after 2 hr of exposure and at 100 microMols after 4 hr exposure. PCBP, on the other hand, did not affect LDH leakage even at 200 microMols for up to 4 hr. Although both congeners increased cerebellar granule cell (Ca(2+))i, DCPB was more effective in increasing (Ca(2+))i to a greater extent than PCBP. The increase in (Ca(2+))i produced by both congeners was not transient, but a steady rise was observed with time. The results of this study support the hypothesis that the position of chlorine substitution on the biphenyl ring and/or number of chlorine substitutions may have significant implications for predicting potential effects of PCB congeners in the nervous system, and perturbations in Ca(2+) homeostasis might play a significant role in the neuroactivity of PCBs.