Thresholds in toxic, teratogenic, mutagenic, and carcinogenic effects.

Many inhibitory and toxic effects show a dose dependence for which the extrapolation of a linear plot to zero or background effect cuts through the abscissa at some positive dose, indicating a threshold concentration below which the agent seems to be ineffective (1). If the teratogenic effect of such an agent is caused by the same cellular reaction, its dose-effect curve may also exhibit a threshold, though with a lower value. In contrast, for most mutagenic compounds a linear plot of the frequency of induced mutations against the dose (concentration) has exhibited no threshold; such experiments were done with transforming DNA or bacterial viruses (2-4), bacteria or fungi (5, 6), plants (7-9, Sparrow and Scheirer, personal communication), insects (10), and mammalian test systems (11, 12). An apparent threshold of mutation induction has been observed only rarely, usually where the investigated cells could be reached only after the mutagen had passed several barriers (12, 13). One may therefore ask whether there are fundamental reasons for this different dose response of toxic versus mutagenic effects and under which conditions a threshold effect could be expected. Such considerations are important for the experimental evaluation of the potential hazard of pesticides, drugs, or food additives.