Dose-response and threshold effects in cytotoxicity and apoptosis

Cell death can occur as an active, programmed event in response to cytotoxi c injury or to endogenous growth limiting factors; the latter serve to main tain homeostasis of cell number in tissues. Cells seem to use different pat hways for programmed death, as reflected by their different morphology and different biochemistry. Severe cell damage leading to incapacitation of ess ential cell functions such as ATP synthesis or the maintenance of membrane potential may lead to "necrosis". In any event, the incidence and rate of c ell death increase with increasing signal intensity. Cytotoxic injury requi res a certain number of primary insults; cell death will therefore occur on ly beyond a definable threshold. Growth factor control of cell death is rec eptor-mediated with dose-response relations including threshold phenomena f ollow the general principles of receptor kinetics. The occurrence of progra mmed cell death during the stages of carcinogenesis introduces a reversible component into this disease. Therefore, there may exist thresholds of dose or durations of exposure to certain carcinogens below which irreversible d isease is not generated. (C) 2000 Elsevier Science B.V. All rights reserved .