Critique of the linear theory of carcinogenesis.

1) Present data on human leukemogenesis by radiation fail to indicate a linear relation between dose and effect. Because data are scanty, such a hypothesis cannot be ruled out statistically, but it is less probable than a nonlinear or threshold relation. 2) Other instances in which carcinogenic agents have been examined from the standpoint of dose and dose-rate relations show many clear instances where the relation is nonlinear and none in which linearity is unquestionably demonstrated. 3) Theoretical consideration of the probability that a single critical molecular event, such as a mutation, will give rise to cancer indicate that a malignant change must be an extraordinarily improbable result of such a perturbation. It is also very difficult to reconcile this mechanism with the rather comparable spontaneous and induced-cancer incidences in species with greatly different numbers of cells. 4) Any scheme in which multiple events caused by the carcinogen are required to produce a tumor is incompatible with a linear relation, while, if a disordered state of tissue is an important factor, a true threshold may even occur. There is much evidence, from cancer research of all sorts, indicating that one or both of these conditions is involved in the carcinogenic process.