Assessing the Safety of Vitamin A Delivered Through Large-Scale Intervention Programs: Workshop Report on Setting the Research Agenda.

BACKGROUND: Vitamin A (VA) deficiency (VAD) is still a concern in many parts of the world, and multiple intervention strategies are being implemented to reduce the prevalence of VAD and associated morbidity and mortality. Because some individuals within a population may be exposed to multiple VA interventions, concerns have been raised about the possible risk of hypervitaminosis A. OBJECTIVES: A consultative meeting was held in Vienna, Austria, in March 2014 to (1) review current knowledge concerning the safety and effectiveness of large-scale programs to control VAD, (2) develop a related research agenda, and (3) review current available methods to assess VA status and risk of hypervitaminosis A. METHODS: Multiple countries were represented and shared their experiences using a variety of assessment methods, including retinol isotope dilution (RID) techniques. Discussion included next steps to refine assessment methodology, investigate RID limitations under different conditions, and review programmatic approaches to ensure VA adequacy and avoid excessive intakes. RESULTS: Fortification programs have resulted in adequate VA status in Guatemala, Zambia, and parts of Cameroon. Dietary patterns in several countries revealed that some people may consume excessive preformed VA from fortified foods. CONCLUSION: Additional studies are needed to compare biomarkers of tissue damage to RID methods during hypervitaminosis A and to determine what other biomarkers can be used to assess excessive preformed VA intake.

Individualized vitamin A supplementation for patients with cystic fibrosis.

BACKGROUND & AIMS: To determine the vitamin A status and appropriate supplementation dosage of cystic fibrosis (CF) patients who received vitamin A supplementation based on annual serum retinol measurements. METHODS: Vitamin A food intake, supplementation dosage, and serum retinol levels were obtained for 32 CF patients >4 years of age (4.3-27.3 years old) who had pancreatic insufficiency and mild-to-moderate lung disease (percent predicted of forced expiratory volume in 1 s > 40%). These measurements were compared with the dietary reference intake for healthy children and adults (D-A-CH dietary recommendations), US and German CF recommendations, and serum retinol concentrations from National Health and Nutrition Examination Survey (NHANES) data. RESULTS: Total vitamin A intake from food and supplementation was 315% ± 182% of D-A-CH recommendations, with 65% from supplements. The range of the prescribed vitamin A supplementation dosage was 0-20,000 IU/day (median 5500 IU), and it was consistent with CF recommendations in 28% of participants. A quarter of all patients did not need any vitamin A supplementation. The total vitamin A intake exceeded the recommended upper limit of intake in 69% of subjects. The mean (range) serum retinol was 38.6 µg/dl (22.1-59.1 µg/dl). All subjects had serum retinol levels above 20 µg/dl and below 72 µg/dl (95th percentile of NHANES reference range). CONCLUSION: Individualized vitamin A supplementation of 0-20,000 IU/day based on annual serum retinol measurements may prevent deficiency and high serum retinol levels, but it may lead to vitamin A intake above the tolerable upper intake level.

Hepatoprotective and immunological functions of Nigella sativa seed oil against hypervitaminosis A in adult male rats.

PURPOSE: The toxic effects of excess vitamin A (VA) intake deserve increased attention. Nigella sativa (NS) seed possesses physiological and pharmacological actions and protects against toxic agents. This work investigated the availability of NS seed oil as a protective agent against the effects of hypervitaminosis A (HVA) on liver function and immunity. METHODS: Fifty adult albino rats were used and divided into five groups: (G1) control; (G2) experimental HVA rats administered extreme doses (10,000 IU/kg body weight) of VA oil orally, daily for 6 weeks; (G3) rats treated with NS seed oil (800 mg/kg) orally, daily for 6 weeks; (G4) HVA rats simultaneously treated with NS seed oil at the same doses and periods; and (G5) HVA recovery group. Liver function, immunoglobulin (IgG and IgM) levels, and lysosome activity were measured in serum. RESULTS: HVA rats revealed marked elevations in alanine aminotransferase and aspartate aminotransferase activities. This is the first study to demonstrate that NS seed oil possesses significant hepatoprotective activity against HVA. NS seed oil was a potent inducer of IgG and IgM in rat serum either alone or with high doses of VA. CONCLUSIONS: These findings may be considered the initial steps of the physiological and humoral immune responses for NS seed oil against HVA, but further studies examining longer periods are needed prior to recommending the use of NS seed oil as an alternative medicine for hepatic and immune diseases.

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(-1). d(-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 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 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.

Alleviation of vitamin A deficiency with palm fruit and its products.

The decreased dietary diversity wrought from the adoption of the settled, agrarian system to replace the hunter-gather and pastoralist lifestyles assured a stable supply of protein and calories from grains and tubers while creating a vulnerability for humans to suffer micronutrient deficiencies. The vitamin A from animal tissue is more bioavailable to humans than the provitamin A in the matrix of green plants. Provitamin A carotenes achieve a dietary vitamin A efficacy nearly equivalent to that of the preformed vitamin only in the context of an oily matrix. The homeostatic regulation of carotene bioconversion by the intestine, moreover, prevents any excess toxic accumulation of vitamin A from provitamin A sources. The efficacy and safety of the palm fruit (genus Elaeis) as a source of vitamin A, in addition to its cultural recognition as a food, are more consistent with the gentler concept of "alleviation" of the public health problem of hypovitaminosis A, then the more aggressive, medical model of "eradication" with its greater potential for risk and collateral damage. The palm fruit and its derivatives achieve new opportunities for creative contribution and sustained use in formats of supplementation (prophylactic in children and women, for lactation), food-to-food fortification (in bakery goods and snacks, as condiments), and even in food diversification strategies. Experience in India, South Africa, and Guatemala begins to define and delineate the opportunities and limitations for the palm fruit to contribute to the alleviation of endemic vitamin A deficiency.