Vitamin A is required in small amounts in crucial biological processes such as controlling the differentiation and proliferation of epithelial cells, maintaining general growth and visual and reproductive functions. Therapeutically, vitamin A is used in dermatology for curing various skin diseases, and one of the metabolites of retinol, all-trans retinoic acid, is used topically to treat acne. Vitamin A, as retinyl esters, is also taken in various amounts as a food supplement.
The recommended average daily dietary intake of vitamin A was estimated by Sauberlich et al. (1974) at 600 retinol equivalents (RE) per day for adult men. Olsen (1987) estimated a total amount of 625 RE per day on the basis of metabolic turnover data. Adequate levels of vitamin A intake must be such that the concentration in the liver is maintained at 20 RE per g. From these data the regulatory authorities of the US and Canada recommended the following daily intake of vitamin A: male adults and pregnant women: 1000 RE per day, female adults: 800 RE per day, lactating women 1250 RE per day, and children of 1 to 3 yr 400, 4 to 6 yr 500, and 7 to 9 yr 700 RE per day.
One of the most important toxic effects occurring after chronic and/or acute hypervitaminosis A is teratogenicity in early pregnancy. Rosa et al. (1986) described 18 cases of teratogenic effects in humans caused by hypervitaminosis A. Acute and chronic hypervitaminosis A may be caused by consuming vitamin A as a food supplement, or in liver. The vitamin preparations on the Dutch market, for example, contain from 300 RE to 15,000 RE vitamin A per dosing unit. Livers of calves may contain even more, 25,000 RE per 100 g!
From these data it is clear that women who are on a normal or rich diet with respect to the intake of vitamin A run a high risk by consuming liver or vitamin preparations in early pregnancy. Since only few human data are available, especially on the teratogenic effect, risk assessment is based on data obtained in animal studies. To estimate this risk a good interspecies extrapolation model is needed to extrapolate these data to the human situation.
Table 18.1 lists the lowest teratogenic doses of vitamin A in several species. The data clearly show a large interspecies variability in sensitivity to vitamin A.
The differences in route of administration (oral vs. intraperitoneal) and in kinetics of vitamin A may cause interspecies variability. Further, the fact that different effects were measured may play a role. There may also be interspecies differences in morphology of the uterus.
Table 18.1Lowest teratogenic dose of vitamin A in various species after oral (p.o) or intraperitoneal (i.p.) administration
Species (body weight)
Time after conception (days)
Man (60 kg) 120 p.o 14-35 Cranium and face
Hamster (100 g) 30,000 p.o 8 Exencephalum
Rat (200 g) 50,000 p.o 9-11 Exencephalum
184.108.40.206 Toxicokinetics As mentioned above, one of the causes of the interspecies' differences shown in Table 18.1 may be found in species' differences in toxicokinetic behavior of vitamin A. Therefore, the toxicokinetics of vitamin A and its precursors are briefly discussed here.
In the lumen of the gastro-intestinal tract, retinyl esters are hydrolyzed and the retinol formed is taken up by the enterocytes by means of passive diffusion. In contrast, caro-tenoids are taken up as such and converted to retinol in the enterocytes by cleavage.
O R all - trans retinoyl esters
O R all - trans retinoyl esters all - trans retinal
all - trans retinal
all - trans retinoic acid
all - trans retinoic acid
In the enterocytes, retinol is re-esterified by two specific enzymes and the resulting retinyl esters are incorporated in the chylomicrons, followed by secretion in the lymph and transport to the liver via the thoracic lymph duct and systemic circulation. In the liver 10% of the total amount of the retinyl esters are stored in parenchymal cells and 90% in fat-storing cells. After hydrolysis and binding to specific proteins, retinol and retinoic acid are secreted into the blood and distributed to other organs. If the recommended amount of vitamin A is consumed, the amount in the liver remains constant and the blood concentrations of retinol and retinoic acid remain low. After intake of excessive amounts most processes, such as uptake, esterification, hydrolysis, and binding to proteins may become saturated, leading to an increase in the free retinol concentration and induction of toxic effects.
For the development of an extrapolation model to assess the teratological risk from vitamin A, the following toxicokinetic aspects must be examined in more detail in at least two species: linearity of absorption, bioavailability of retinol after administration of carotenoids or retinyl esters, and capacity of the liver to store retinol and to synthesize the relevant binding proteins. Also, concentration and form of vitamin A that the embryo is exposed to in the case of acute or chronic hypervitaminosis A are of high importance. If these toxicokinetic aspects of vitamin A are elucidated and can be related to physiological and biochemical characteristics, such as lymph flow, blood flow, and enzyme activities of the animals used, extrapolation to humans and an estimate of the risk can be achieved.
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