Vitamin A teratogenicity and risk assessment in the macaque retinoid model

Studies were performed in the cynomolgus monkey (Macaca fascicularis) to pr ovide risk assessment information on safe dose levels of Vitamin A during h uman pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg ( 2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy ( gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, al l-trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-relate d increase in abortion and malformation that affected typical retinoid targ et tissues in the embryo, including the craniofacial region, heart, and thy mus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 2 0 000 IU/kg (6 mg/kg), respectively. A companion study involving oral admin istration of 13-cis-RA during the same gestational period established the N OAEL for malformations at 0.5 mg/kg/day, which is close to the human therap eutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopath y. Based on the known similarities in teratogenic susceptibility to 13-cis- RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe l evels of this nutrient in humans applying a safety factor of 10, This appro ach yielded safe levels of Vitamin A during human pregnancy in the range of similar to 25 000 to 37 000 IU/day. (C) 2000 Elsevier Science Inc. All rig hts reserved.