Abstract

Six known teratogens, trypan blue, hypervitaminosis A, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil and actinomycin D, have been administered in pairs at low dosage levels to female rats on the 8th or 9th days of pregnancy. Gestation was terminated on the 20th day and the conceptuses examined for intrauterine death and for malformations.

All pairs of agents tested showed appreciable potentiation of teratogenic effect, even when very small doses were used, provided the dosage was above an arbitrary threshold level. No such consistent pattern of interaction was observed as regards intrauterine death.

In several instances significant potentiation occurred when one of two agents was used at subthreshold and the other at low suprathreshold level.

In two instances, namely, actinomycin D with 5-fluorouracil and actinomycin D with cyclophosphamide, potentiation was observed when both agents were used at subthreshold or barely threshold levels. When these three agents were employed simultaneously at threshold and sub-threshold levels a still higher degree of potentiation resulted.

It is thus established that chemical teratogenic agents can be used in certain combinations at low, even subthreshold dosages, to produce malformations at a rate considerably above the rate expected when only one agent is used alone. This may serve as a model for explaining some of the presently unaccounted for human malformation.