Previous studies have shown that whole toxicity in the Naugatuck River, Connecticut, does not exhibit additive behavior. The nature of whole toxicity in the river is reassessed using available water chemistry data to identify the primary toxicants and quantify their interactions in the river. Two major classes of toxicity—copper from industrial discharges and toxicity from publicly owned treatments works (POTWs)—are identified. A water quality model of whole toxicity is constructed, based on the analysis of specific toxicant data. The results are in closer agreement with observed instream toxicity than the previous model which assumed strict additivity of effluent toxicity.