- The mechanisms of acute copper and silver toxicity in freshwater organisms appear similar. Both result in inhibition of branchial sodium (and chloride) uptake initiating a cascade of effects leading to mortality. The inhibition of the branchial Na/K-ATPase in the basolateral membrane is generally accepted as the key component responsible for the reduced sodium uptake. We propose that branchial carbonic anhydrase and the apical sodium channel may also be important targets for both copper and silver exposure. Several attempts have been made to predict metal sensitivity. A prominent example is the geochemical-biotic ligand model. The geochemical-biotic ligand modeling approach has been successful in explaining variations in tolerance to metal exposure for specific groups of animals exposed at different water chemistries. This approach, however, cannot explain the large observed variation in tolerance to these metals amongst different groups of freshwater animals (i.e. Daphnia vs. fish). Based on the detailed knowledge of physiological responses to acute metal exposure, the present review offers an explanation for the observed variation in tolerance. Smaller animals are more sensitive than large animals because they exhibit higher sodium turnover rates. The same relative inhibition of sodium uptake results in faster depletion of internal sodium in animals with higher sodium turnover. We present a way to improve predictions of acute metal sensitivity, noting that sodium turnover rate is the key predictor for variation in acute copper and silver toxicity amongst groups of freshwater animals. We suggest that the presented sodium turnover model is used in conjunction with the Biotic Ligand Model for risk management decisions.