IS THERE A NO-EFFECT DOSE FOR CORTICOSTEROID-INDUCED CLEFT-PALATE - THE CONTRIBUTION OF ENDOGENOUS CORTICOSTERONE TO THE INCIDENCE OF CLEFT-PALATE IN MICE

Teratology and genetic counselors are frequently asked whether very lo w exposures of drugs and chemicals can cause a child's congenital malf ormations. One critical factor on which the counseling is based is the dose. Because teratogenic effects follow a toxicologic dose-response curve with a no-effect dose, frequently counselors can refute a causal relationship because the dose was far below the no-observable-effect dose. Recently, some investigators have suggested that some teratogens which are present in physiologic levels such as cortisone, glucose, i nsulin, or sex steroids may contribute to the background incidence of congenital malformations and, therefore, there is no safe dose. Using corticosteroid-induced cleft palate in mice as the model, we conducted experiments to test this hypothesis. Adrenalectomy of A/J or CD-1 dam s resulted in a reduction of endogenous corticosterone, but did not re duce the spontaneous incidence of cleft palate in the offspring. In A/ J mice, the incidence of isolated cleft palate increased with adrenale ctomy indicating that the spontaneous incidence of this defect is not due to endogenous corticosterone. Adrenalectomy did not affect the sus ceptibility of CD-1 mice to cortisone induced cleft palate demonstrati ng that endogenous corticosterone did not contribute significantly to the incidence of cleft palate induced by the exogenous corticosteroid. Finally, results in CD-1 mice clearly indicate that cortisone, like o ther teratogens, has a no-effect level for teratogenesis. These studie s support the concept of a threshold in the dose-response relationship for corticosteroid-induced cleft palate in mice.