The molecular basis of stochastic and nonstochastic effects

Stochastic effects have been defined as those for which the probability increases with dose, without a threshold. Nonstochastic effects are those for which incidence and severity depends on dose, but for which there is a threshold dose. These definitions suggest that the two types of effects are not related. In this paper it will be shown that at least some of the nonstochastic effects are the consequence of accumulated stochastic effects and that both types of effect can be related to a common cellular damage. It is proposed that, at the cellular level, effects such as mutation induction and cell reproductive death are related to DNA double-strand breaks caused by radiation. Further, we propose that stochastic effects depend on a mutational event induced in a critical cell of a target organ. Nonstochastic effects are considered to arise because the function of a substantial proportion of critical cells is impaired. In some cases the predominant effect is comparable to cell reproductive death. Animal mortality, for instance, may occur because a substantial proportion of bone marrow cells is killed. Using this concept, mathematical formulas can be derived for the various effects. Modification of the irradiation conditions (e.g., low dose rate or density ionizing radiation) leads to changes in the initial molecular lesions and, consequently, to changes in the dose effect relationships of stochastic and nonstochastic effects. Experimental support will be discussed, using animal mortality as an endpoint. The implications of this approach will be discussed with emphasis on its application to radiological protection.