A physico-chemical model of the fate of toxic substances in the Great Lakes is constructed from mass balance principles and incorporates principal mechanisms of particulate sorption-desorption, sediment-water and atmosphere-water interactions, and chemical and biochemical decay. Calibration of the toxic model is through comparison to plutonium-239 data collected in the 1970s using a 23 year time variable calculation and indicates that in general, the sediments are interactive with the water column in the Great Lakes through resuspension and or horizontal transport. Fifty percent response times of 239Pu following a cessation of load extend beyond 10 years with sediment resuspension. The calibration model was applied to polychlorinated biphenyl (PCB) using a high and low estimate of contemporary external load and with and without volatilization. Calibration of the model to data on benzo(a)pyrene confirms that on a lake-wide scale the principal external source in the atmosphere and for the larger lakes such as Michigan the response time of the lake to external loads is about 6-10 years while for Lake Erie response time is about 2 years. Application of the model to cadmium in the lakes, using a solids dependent partition coefficient indicates that the lakes do not reach equilibrium over a 100 year period. Calculated high concentrations of cadmium in interstitial water (e.g., 10 microgram/l) indicate the importance of measuring interstitial cadmium concentrations.