The aim of this study was to determine whether the cadmium-induced cellular stress response can be modulated by the subsequent application of low concentrations of the same ion. It is shown that exposure of Reuber H35 rat hepatoma cells to cadmium concentrations of 10 or 30 microM for 1 h leads to a biphasic change in their sensitivity towards a second exposure to cadmium, an initial sensitization is followed by development of tolerance towards the secondary treatment with cadmium. Furthermore, incubations for 1 h in the presence of 10 microM of cadmium induce the synthesis of the major heat shock proteins except for hsp60. A step-down cadmium regime, i.e. a pretreatment of 1 h with 10 or 30 microM immediately followed by incubations with lower concentrations of cadmium (ranging from 0.03 to 1 microM), leads to additional increases in hsp synthesis. Since no effect of these low concentrations was observed on hsp synthesis in non-pretreated cells, the effect of a step-down treatment thus results in a higher effect on hsp synthesis than could be expected based on their summation. The sensitized cells also develop a higher level of tolerance in the presence of the above mentioned low concentrations of cadmium. It can be concluded that during the transient period of enhanced sensitivity, low concentrations of the original stressor enhance the synthesis of hsps and thus induce higher levels of tolerance in comparison with cells which only received the primary cadmium treatment.