MODEL PREDICTING THE TERATOGENIC POTENTIAL OF RETINYL PALMITATE, USING A COMBINED IN-VIVO IN-VITRO APPROACH

Retinyl palmitate (RP) is a known laboratory animal teratogen inducing abnormalities of the second visceral arch when administered on day 9 of gestation in the rat. However, there are significant problems when attempting to extrapolate this result to the human. A combined in vive /in vitvo model was developed to assist in human risk assessment. The in vitro teratogenic threshold concentration of a number of retinyl pa lmitate metabolites was established. Serum concentrations of retinyl p almitate metabolites fallowing a single teratogenic dose of RP in the pregnant vat were also measured. These dosed sera were also used to cu lture rat embryos. Our hypothesis was that malformations would only be induced by the dosed sera in vitvo if the threshold concentration(s) of one or more metabolites was exceeded. Using this approach, lit was determined that the teratogenicity of the sera were best predicted by serum retinol levels, with some indication that all-trans-retinoic aci d and 4-oxo-all-trans-retinoic acid could be involved in some cases. T he available human data suggest that threshold concentrations of these retinoids were unlikely to be exceeded following vitamin A supplement s of 25,000 IU/day. While the proposed model does not take into accoun t species differences, protein binding, and transfer to the embryo, it does have potential for human risk assessment. (C) 1998 Wiley Liss, I nc.