The biologic and toxic effects of polychlorinated biphenyls (PCBs) are remarkably dependent on their structure. The most toxic PCBs, namely 3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl are substituted in at least one meta and para position on both phenyl rings (i.e., the lateral positions) and contain no ortho-chloro substituents. These three congeners and a fourth PCB, namely 3,4,4',5-tetrachlorobiphenyl, are approximate isostereomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and, in common with TCDD, induce hepatic microsomal benzo[a]pyrene or aryl hydrocarbon hydroxylase (AHH) in rats and rat hepatoma cells in culture. The mono-ortho substituted analogs of the four laterally substituted PCBs also induce microsomal AHH activity and simultaneously enhance microsomal enzyme activities which are inducible by phenobarbitone (PB). This group of PCBs exhibits many of the properties of 2,3,7,8-TCDD and related polychlorinated dibenzo-p-dioxins; there is a close parallel in the relative potencies of these PCBs for AHH induction and their binding affinities for the Ah receptor protein and some of these PCBs are also toxic. Preliminary studies on other halogenated biphenyls confirm that the polarizability of a lateral substituent is an important factor in their activity as AHH inducers (i.e., I greater than Br greater than Cl greater than F). However, preliminary results with other substituted halogenated biphenyls suggest that additional structural factors are also important in determining the activity of these compounds.