Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations

Background: It is well established that an excessive intake of retinol (vitamin A) is toxic; however, it has been > 25 y since the last extensive treatise of case reports on this subject. Objective: The objectives were to identify and evaluate all individual cases of retinol toxicity published in the scientific literature that assessed the thresholds and symptoms induced by high intakes of retinol and to compare the toxicity of different physical forms of retinol preparations. Design: We performed a meta-analysis of case reports on toxicity claimed to be induced by intakes of excessive amounts of dietary retinol (ie, retinol and retinyl esters in foods or supplements). Using free text and MESH (medical subheading) strategies in PubMed, we identified 248 articles in the scientific literature. From these initial articles we identified other relevant citations. The final database consisted of 259 cases in which individual data on dose, sex, age, time of exposure, and symptoms are reported. Results: Chronic hypervitaminosis A is induced after daily doses of 2 mg retinol/kg in oil-based preparations for many months or years. In contrast, doses as low as 0.2 mg retinol * [kg.sup.-1] * [d.sup.-1] in water-miscible, emulsified, and solid preparations for only a few weeks caused chronic hypervitaminosis A. Thus, water-miscible, emulsified, and solid preparations of retinol are [approximately equal to] 10 times as toxic as are oil-based retinol preparations. The safe upper single dose of retinol in oil or liver seems to be [approximately equal to] 4-6 mg/kg body wt. These thresholds do not vary considerably with age. Conclusions: The results of the present study indicate that the physical form of retinol supplements is a major determinant of toxicity. The use of water-miscible, emulsified, and solid preparations of retinol should therefore be carefully considered before being used in supplements and fortifications. KEY WORDS Vitamin A toxicity, hypervitaminosis A, fortification, retinol, retinyl esters, water-miscible retinol, emulsified retinol, supplements