Assessments of the effects of exposure of human populations to complex environmental contaminants, such as those found in contaminated fish, necessitate the investigation of contaminant interactions. We have recently demonstrated that polychlorinated biphenyls (PCBs) and methylmercury (MeHg) synergistically reduce rat brain striatal slice dopamine (DA) and increase media DA concentrations in vitro. To better understand the mechanism(s) by which these effects occur we examined the effects of these two contaminants, either alone or in combination, on intracellular calcium concentrations ([Ca2+]) in rat cerebellar granule cells using flow cytometry. Exposure of granule cells to either 2,2'-dichlorobiphenyl (2,2'-DCB) or MeHg dose-dependently increased [Ca2+]i. Granule cells exposed to 1.5 microM MeHg and 2.5 or 5.0 microM 2,2'-DCB showed synergistic increases in [Ca2+]i which were greatest at exposure times of 5 and 10 min. Higher dose combinations, including 2.0 microM MeHg and 10 or 20 microM 2,2'-DCB, or longer duration of exposure to lower concentrations of contaminant mixtures, reduced [Ca2+]i in the granule cells compared to elevations seen following exposure to MeHg only, suggesting a dose-dependent antagonism between PCBs and MeHg. These data provide evidence for the synergistic and antagonistic interactions of PCBs and MeHg at the level of [Ca2+]i regulation that may ultimately lead to alterations in cellular function, including changes in dopamine regulation.