and liver abnormalities. reduced bone mineral density was considered, but dismissed because the human evidence was contradictory. during pregnancy, especially during the first trimester, consumption of retinol in amounts exceeding 4,500 μg/day increased the risk of birth defects, but not below that amount, thus setting a "no-observed adverse-effect level" (noael). given the quality of the clinical trial evidence, the noael was divided by an uncertainty factor of 1.5 to set the ul for women of reproductive age at 3,000 μg/day of preformed vitamin a. for all other adults, liver abnormalities were detected at intakes above 14,000 μg/day. given the weak quality of the clinical evidence, an uncertainty factor of 5 was used, and with rounding, the ul was set at 3,000 μg/day. despite a us ul set at 3,000 μg, it is possible to buy over-the-counter dietary supplement products which are 7,500 μg (25,000 iu), with a label caution statement "not intended for long term use unless under medical supervision." for children, uls were extrapolated from the adult value, adjusted for relative body weight. for infants, several case studies reported adverse effects that include bulging fontanels, increased intracranial pressure, loss of appetite, hyperirritability and skin peeling after chronic ingestion of the order of 6,000 or more μg/day. given the small database, an uncertainty factor of 10 divided into the "lowest-observed-adverse-effect level" (loael) led to a ul of 600 μg/day. β-carotene safety no adverse effects other than carotenemia have been reported for consumption of β-carotene rich foods. supplementation with β-carotene does not cause hypervitaminosis a. two large clinical trials (atbc and caret) were conducted in tobacco smokers to see if years of β-carotene supplementation at 20 or 30 mg/day in oil-filled capsules would reduce the risk of lung cancer. these trials were implemented because observational studies had reported a lower incidence of lung cancer in tobacco smokers who had diets higher in β-carotene. unexpectedly, this high-dose β-carotene supplementation resulted in a higher incidence of lung cancer and of total mortality. taking this and other evidence into consideration, the u.s. institute of medicine decided not to set a tolerable upper intake level (ul) for β-carotene. the european food safety authority, acting for the european union, also decided not to set a ul for β-carotene. carrots are a rich source of beta-carotene carotenosis carotenoderma, also referred to as carotenemia, is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. it is associated with a high blood β-carotene value. this can occur after a month or two of consumption of beta-carotene rich foods, such as carrots, carrot juice, tangerine juice, mangos, or in africa, red palm oil. β-carotene dietary supplements can have the same effect. the discoloration extends to palms and soles of feet, but not to the white of the eye, which helps distinguish the condition from jaundice. consumption of greater than 30 mg/day for a prolonged period has been confirmed as leading to carotenemia. u.s. labeling for u.s. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value (%dv). for vitamin a labeling purposes 100% of the daily value was set at 5,000 iu, but it was revised to 900 μg rae on 27 may 2016. a table of the old and new adult daily values is provided at reference daily intake. sources food μg rae (2001) per 100 g cod liver oil30000 beef liver (cooked)21145 chicken liver (cooked)4296 butter (stick)684 cheddar cheese316 egg (cooked)140 vitamin a is found in many foods. vitamin a in food exists either as preformed retinol – an active form of vitamin a – found in animal liver, dairy and egg products, and some fortified foods, or as provitamin a carotenoids, which are plant pigments digested into vitamin a after consuming carotenoid-rich plant foods, typically in red, orange, or yellow colors. carotenoid pigments may be masked by chlorophylls in dark green leaf vegetables, such as spinach. the relatively low bioavailability of plant-food carotenoids results partly from binding to proteins – chopping, homogenizing or cooking disrupts the plant proteins, increasing provitamin a carotenoid bioavailability. vegetarian and vegan diets can provide sufficient vitamin a in the form of provitamin a carotenoids if the diet contains carrots, carrot juice, sweet potatoes, green leafy vegetables such as spinach and kale, and other carotenoid-rich foods. in the u.s., the average daily intake of β-carotene is in the range 2–7 mg. some manufactured foods and dietary supplements are sources of vitamin a or beta-carotene. despite the us setting an adult upper limit of 3,000 μg/day, some companies sell vitamin a as a dietary supplement with amounts of 7,500 μg/day. two examples are wonderlabs and pure prescriptions. fortification some countries require or recommend fortification of foods. as of january 2022, 37 countries, mostly in sub-saharan africa, require food fortification of cooking oil, rice, wheat flour or maize (corn) flour with vitamin a, usually as retinyl palmitate or retinyl acetate. examples include pakistan, oil, 11.7 mg/kg and nigeria, oil, 6 mg/kg; wheat and maize flour, 2 mg/kg. an additional 12 countries, mostly in southeast asia have a voluntary fortification program. for example, the government of india recommends 7.95 mg/kg in oil and 0.626 mg/kg for wheat flour and rice. however, compliance in countries with voluntary fortification is lower than countries with mandatory fortification. no countries in europe or north america fortify foods with vitamin a. food μg rae (2001) per 100 g sweet potato, baked, no added fat 957 carrot, frozen, cooked, no added fat 843 pumpkin, canned, cooked 767 spinach, fresh, cooked, no added fat 341 kale, fresh, cooked, no added fat 245 separated from fortification via addition of synthetic vitamin a to foods, means of fortifying foods via genetic engineering have been explored. research on rice began in 1982. the first field trials of golden rice cultivars were conducted in 2004. the result was "golden rice", a variety of oryza sativa rice produced through genetic engineering to biosynthesize beta-carotene, a precursor of retinol, in the edible parts of rice. in may 2018, regulatory agencies in the united states, canada, australia and new zealand had concluded that golden rice met food safety standards. on 21 july 2021, the philippines became the first country to officially issue the biosafety permit for commercially propagating golden rice. vitamin a supplementation (vas) vitamin a supplementation coverage rate (children ages 6–59 months), 2014 delivery of oral high-dose supplements remains the principal strategy for minimizing deficiency. as of 2017, more than 80 countries worldwide are implementing universal vas programs targeted to children 6–59 months of age through semi-annual national campaigns. doses in these programs are one dose of 50,000 or 100,000 iu for children aged 6 to 11 months and 100,000 to 200,000 iu for children aged 12 months to five years, every four to six months. deficiency main article: vitamin a deficiency primary causes vitamin a deficiency is common in developing countries, especially in sub-saharan africa and southeast asia. deficiency can occur at any age, but is most common in pre-school-age children and pregnant women, the latter due to a need to transfer retinol to the fetus. the causes are low intake of retinol-containing, animal-sourced foods and low intake of carotene-containing, plant-sourced foods. vitamin a deficiency is estimated to affect approximately one third of children under the age of five around the world, possibly leading to the deaths of 670,000 children under five annually. between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin a deficiency. vitamin a deficiency is "the leading cause of preventable childhood blindness", according to unicef. it also increases the risk of death from common childhood conditions, such as diarrhea. unicef regards addressing vitamin a deficiency as critical to reducing child mortality, the fourth of the united nations' millennium development goals. during diagnosis, night blindness and dry eyes are signs of vitamin a deficiency that can be recognized without requiring biochemical tests. plasma retinol is used to confirm vitamin a status. a plasma concentration of about 2.0 μmol/l is normal; less than 0.70 μmol/l (equivalent to 20 μg/dl) indicates moderate vitamin a deficiency, and less than 0.35 μmol/l (10 μg/dl) indicates severe vitamin a deficiency. breast milk retinol of less than 8 μg/gram milk fat is considered insufficient. one weakness of these measures is that they are not good indicators of liver vitamin a stores as retinyl esters in hepatic stellate cells. the amount of vitamin a leaving the liver, bound to retinol binding protein (rbp), is under tight control as long as there are sufficient liver reserves. only when liver content of vitamin a drops below approximately 20 μg/gram will concentration in the blood decline. secondary causes there are causes for deficiency other than low dietary intake of vitamin a as retinol or carotenes. adequate dietary protein and caloric energy are needed for a normal rate of synthesis of rbp, without which, retinol cannot be mobilized to leave the liver. systemic infections can cause transient decreases in rbp synthesis even if protein-calorie malnutrition is absent. chronic alcohol consumption reduces liver vitamin a storage. non-alcoholic fatty liver disease (nafld), characterized by the accumulation of fat in the liver, is the hepatic manifestation of metabolic syndrome. liver damage from nafld reduces liver storage capacity for retinol and reduces the ability to mobilize liver stores to maintain normal circulating concentration. animal requirements all vertebrate and chordate species require vitamin a, either as dietary carotenoids or preformed retinol from consuming other animals. deficiencies have been reported in laboratory-raised and pet dogs, cats, birds, reptiles and amphibians, also commercially raised chickens and turkeys. herbivore species such as horses, cattle and sheep can get sufficient β-carotene from green pasture to be healthy, but the content in pasture grass dry due to drought and long-stored hay can be too low, leading to vitamin a deficiency. omnivore and carnivore species, especially those toward the top of the food chain, can accrue large amounts of retinyl esters in their livers, or else excrete retinyl esters in urine as a means of dealing with surplus. before the era of synthetic retinol, cod liver oil, high in vitamins a and d, was a commonly consumed dietary supplement. invertebrates cannot synthesize carotenoids or retinol, and thus must accrue these essential nutrients from consumption of algae, plants or animals. medical uses preventing and treating deficiency main article: vitamin a deficiency recognition of its prevalence and consequences has led to governments and non-government organizations promoting vitamin a fortification of foods and creating programs that administer large bolus-size oral doses of vitamin a to young children every four to six months. in 2008, the world health organization estimated that vitamin a supplementation over a decade in 40 countries averted 1.25 million deaths due to vitamin a deficiency. a cochrane review reported that vitamin a supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children ages six month to five years of age. all-cause mortality was reduced by 14%, and incidences of diarrhea by 12%. however, a cochrane review by the same group concluded there was insufficient evidence to recommend blanket vitamin a supplementation for infants one to six months of age, as it did not reduce infant mortality or morbidity. oral retinoic acid orally consumed retinoic acid (ra), as all-trans-tretinoin or 13-cis-isotretinoin has been shown to improve facial skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells. ra reduces the size and secretion of the sebaceous glands, and by doing so reduces bacterial numbers in both the ducts and skin surface. it reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils. in the us, isotretinoin was released to the market in 1982 as a revolutionary treatment for severe and refractory acne vulgaris. it was shown that a dose of 0.5‑1.0 mg/kg body weight/day is enough to produce a reduction in sebum excretion by 90% within a month or two, but the recommended treatment duration is 4 to 6 months. isotretinoin is a known teratogen, with an estimated 20‑35% risk of physical birth defects to infants that are exposed to isotretinoin in utero, including numerous congenital defects such as craniofacial defects, cardiovascular and neurological malformations or thymic disorders. neurocognitive impairments in the absence of any physical defects has been