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 vivo/in vitro model was developed to assist in human risk assessment. The in vitro teratogenic threshold concentration of a number of retinyl palmitate metabolites was established. Serum concentrations of retinyl palmitate metabolites following a single teratogenic dose of RP in the pregnant rat were also measured. These dosed sera were also used to culture rat embryos. Our hypothesis was that malformations would only be induced by the dosed sera in vitro if the threshold concentration(s) of one or more metabolites was exceeded. Using this approach, it was determined that the teratogenicity of the sera were best predicted by serum retinol levels, with some indication that all-trans-retinoic acid and 4-oxo-all-trans-retinoic acid could be involved in some cases. The available human data suggest that threshold concentrations of these retinoids were unlikely to be exceeded following vitamin A supplements of 25,000 IU/day. While the proposed model does not take into account species differences, protein binding, and transfer to the embryo, it does have potential for human risk assessment.
Ritchie
H E
HE
Department of Biomedical Sciences, University of Sydney, Australia.
Webster
W S
WS
Eckhoff
C
C
Oakes
D J
DJ
D000818:Animals; D046508:Culture Techniques; D004224:Diterpenes; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D008954:Models, Biological; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000084562:Retinyl Esters; D013723:Teratogens / Q000633:toxicity*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000633:toxicity
D004224:Diterpenes; D000084562:Retinyl Esters; D013723:Teratogens; D014801:Vitamin A; C014794:retinol palmitate