Abstract

Vitamin A is a nutrient that plays an essential role in vision, growth, cell differentiation and reproduction. However, chronical supplementation by means of vitamin preparations or accidental extreme supplementation by eating cooked liver may lead to toxic effects and even to abnormalities in the embryo of a pregnant individual. It is assumed that one of the metabolites of vitamin A, all-trans-retinoic acid, is mainly responsible for these effects. In this report a modeling approach is introduced which can serve as a starting point in the risk assessment for abnormalities in newborn infants. The model is a compromise between conceptual detail and available data. It is implemented in a computer code (SIMUSOLV/ACSL) for simulating various administration scenario's. From the simulations it follows that increased risk is caused by the formation of retinoic acids in the enterocytes of the small gut. Quantitative knowledge on this is lacking. From the literature it appears that the production of retinoic acids increases more than in proportion with increasing dosing level. Therefore, in the model it is assumed that production of acids in the enterocytes is less saturable than the production of retinyl esters. From the simulations it also follows that the way of administration, is of influence because of the time during which vitamin A becomes available for absorption. The latter feature has been actually observed, but to a much larger extent than from the simulations would follow, during experiments on volunteers. A possible explanation is that absorption of vitamin A depends on its matrix (vitamin preparation or, e.g., cooked liver), its release rate in the small intestine, its dosing level or a combination of these three. The model is well applicable for comparing risk considering various administration scenario's. For an absolute risk assessment more quantitative knowledge on absorption and retinoic acid production in the enterocytes is a prerequisite.