Organochlorine (OC) compounds are some of the main toxicants present in the food web and target several cellular systems including the nonspecific immune system. The objective of this study was to test the hypothesis that OC compounds that activate neutrophils share common structural features. Using activation of phospholipase A(2) (PLA(2)) as a marker of neutrophil activation, isolated rat neutrophils were exposed to a variety of OC compounds. The ortho-substituted polychlorinated biphenyl 2,2',4,4'-tetrachlorobiphenyl, the alpha-, delta-, and gamma-isomers of hexachlorocyclohexane (HCCH), p,p'-dichlorodiphenyltrichloroethane (DDT), dieldrin, and chlordane each induced activation of PLA(2) in neutrophils. Beta-HCCH and the non-ortho-substituted 3,3',4,4'-tetrachlorobiphenyl were without effect. PLA(2) activation stimulated by each of the OC compounds was reduced by methyl arachidonyl fluorophosphonate, which inhibits both a cytosolic and a calcium-independent PLA(2) (iPLA(2)), and by E-6-(bromoethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL), a selective inhibitor of iPLA(2). These results suggest that a fraction of the PLA(2) activity stimulated by OC compounds is dependent on iPLA(2). Western analysis confirmed the presence of iPLA(2) in rat neutrophils. Molecular modeling techniques were used to develop structure-activity relationships for the activation of PLA(2) by OC compounds. Superimposing three-dimensional structures, an electrotopological motif shared by all of the active compounds was identified. This motif was absent in the inactive beta-HCCH and 3,3',4,4'-tetrachlorobiphenyl. This motif, which we have called PHEN, is required for the activation of the neutrophil PLA(2) by OC compounds and consists of a planar hydrophobic domain connected rigidly at a perpendicular angle to a halogen atom.