Embryotoxicity and teratogenicity of topical retinoic acid

Abstract

All-trans-retinoic acid is a potent developmental toxicant in all species examined. The teratogenic risk of topical all-trans-retinoic acid is reviewed. Experimental studies are limited because of the high maternal toxicity, including skin irritation, with doses below those resulting in significant teratogenic response with other application routes, such as oral application. The maximal systemic availability reported for transdermal exposure of all-trans-retinoic acid was 5-6% in the rat, 9.6% in the monkey (48% with dermatitic skin) and 5-7% in the human. Oral administration of threshold teratogenic doses of all-trans-retinoic acid (6 mg/kg/day) to Wistar rats and Swiss hare rabbits resulted in embryonic area under the concentration time curve levels (approximately 1,000 ng.h/g) which were 2- to 4-fold higher than the endogenous all-trans-retinoic acid levels; corresponding maternal plasma area under the concentration time curve values were 98 and 321 ng.h/ml in rat and rabbit, respectively. The 4-oxo-metabolite was also found in maternal plasma and embryo. Large, controlled studies on the possible developmental toxicity of topical all-trans-retinoic acid in the human are not available. Isolated case reports appeared in the literature claiming teratogenic outcome resembling effects after oral isotretinoin use or those observed in experimental studies with oral or parenteral all-trans-retinoic acid administration. The dose absorbed from daily cosmetic or therapeutic application of all-trans-retinoic acid is expected to be below 0.015 mg/kg, which is at least 30-fold lower than the lowest teratogenic dose of isotretinoin in the human. Topical all-trans-retinoic acid application did not appreciably alter endogenous plasma retinoid levels. The influence of nutrition, diurnal variation and in particular oral vitamin A supplements are more important determinants of plasma retinoic acid compounds than topical all-trans-retinoic acid. These results imply a low risk of therapeutic or cosmetic application of topical all-trans-retinoic acid. However, the highly specific spatial and temporal distribution of binding proteins and nuclear receptors in the embryo suggests that even small alterations in endogenous levels of all-trans-retinoic acid in the embryo may alter crucial developmental processes such as morphogenes; this aspect should be further investigated.