Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. TOX/2012/16

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

Review of potential risks from high levels of vitamin A in infant nutrition

Introduction

1. The COT has been asked to provide advice on allergenicity of food and toxicity of chemicals in food, in support of a review by the Scientific Advisory Committee on Nutrition (SACN) of Government recommendations on complementary and young child feeding. An initial paper (TOX/2012/03), highlighting some of the areas requiring consideration was discussed by the COT in February, 2012. Members noted that data on exposure of weaning infants to vitamin A from liver and dietary supplements were limited. Toxicological information relevant to infants was also sparse therefore it was agreed that a more in-depth review was needed to consider risks to infants.

Identity

2. Vitamin A is a lipid soluble, light yellow substance, which is an essential micronutrient responsible for promoting normal growth, vision and immunity. Vitamin A is effectively a group of lipid soluble compounds which are related to all-trans- retinol. It can be found in animals and animal-based products, as retinyl esters (most commonly retinyl palmitate), enriched fortified foods and supplements. Vitamin A can lead to adverse effects when there is a deficiency or excess of the nutrient (Perrotta, et al., 2003).

Figure 1: Structural formula of retinol (C20H30O)

3. Collectively, retinol and retinyl esters are preformed vitamin A and are often referred to as retinoids. The highest concentration of retinol can be found in carnivore liver at concentrations ranging from 30,000 to 50,000 µg of retinol per kg, making it the highest source of preformed vitamin A (Allen and Haskell, 2002;Schulz, et al., 2007). Retinyl esters are hydrolysed by retinyl ester hydrolase (REH) enzymes within the gastrointestinal tract lumen to enable absorption to take place (Perrotta, et al., 2003).

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. 4. Provitamin A carotenoids (α- and β-carotene) can be found in a variety of fruits and vegetables. Retinol provides a much higher vitamin A value than provitamin A carotenoids; it is necessary to eat six times as much provitamin A carotenoids to ensure the equivalent value of vitamin A in retinol is met (Perrotta, et al., 2003). Some can be cleaved in the small intestines to become retinol or they are absorbed intact (Perrotta, et al., 2003).

5. Preformed vitamin A can lead to acute toxicity whereas high intake of β- carotene and other provitamin A carotenoids from food have not shown evidence of toxicity although it can lead to a yellow appearance (Allen and Haskell, 2002). The European Union Scientific Committee on Food (SCF) noted that the toxicity of provitamin A carotenoids is different to that of retinoids (SCF, 2002). Consequently, dietary β-carotene and other provitamin A carotenoid intake would not contribute significantly to the toxicity of high intakes of vitamin A.

6. Vitamin A is expressed either as international units (IU) or retinol equivalents (RE). The RE takes into account the different activities and variable absorption of vitamin A and provitamin A carotenoids and is now the widely accepted unit based on a recommendation of the Food Agricultural Organisation (FAO) and World Health Organisation (WHO) (EVM, 2002). For consistency, RE is used in this paper. Generally, the IU value can be calculated by multiplying the RE by 3.33 (Table 1).

Table 1: The widely accepted conversion factors for vitamin A (Perrotta, et al., 2003)

1 RE 1.00 µg retinol 1.78 µg retinyl palmitate 6.00 µg β-carotene 12.00 µg other provitamin A carotenoids 3.33 IU vitamin A activity as retinol 10.00 IU vitamin A activity as β-carotene

7. An infant aged < 6 months is likely to obtain all of its vitamin A as retinol therefore the recommended daily allowance (RDA) of 420 RE is equivalent to 1400 IU (Bendich and Langseth, 1989). If the intake of vitamin A includes a mixture of preformed vitamin A and provitamin A carotenoids, the typical conversion factor is higher than 3.33 (Bendich and Langseth, 1989).

Current advice

8. The reference nutrient intakes (RNIs) for vitamin A are 700 µg RE/day for adult males, 600 µg RE/day for adult females and 350 µg RE/day for infants aged 0- 12 months (SACN, 2005). Pregnant women and those wishing to become pregnant are advised against eating liver or liver products and taking supplements containing vitamin A because it can be teratogenic (SACN, 2005). In relation to high intakes, the current advice for infants is that liver should be avoided if solid foods are introduced before 6 months (DH, 2012). It is recommended that children do not have more than 2

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. one portion of liver per week because it can be harmful in large amounts (Caroline Walker Trust, 2011).

Hazard identification and characterisation

Toxicokinetics

9. Fat-soluble vitamins, including vitamin A, are actively transported across the placenta towards the end of pregnancy (Leaf, 2007). Retinol-binding protein (RBP) binds to free vitamin A (in retinol form) to facilitate it’s transfer to plasma (Perrotta, et al., 2003). Toxicity appears to arise when the amount of vitamin A present exceeds the amount of RBPs and this is as a result of free retinol binding to lipoproteins, which leads to toxic effects after contact with membranes and body cells (Bendich and Langseth, 1989).

10. Olson et al, (1984) measured the vitamin A content in the liver of 170 deceased US children aged 0-15 years, including premature infants. The children had died of various causes including malformations, congenital (n =16), renal malformation (n = 4) and sudden infant death (n=24) (Olson, et al., 1984). Newborn infants generally show liver vitamin A concentrations of ≤ 20 µg RE/g (Olson, et al., 1984). This analysis revealed new born infants aged 0-6 days (n = 22) to have a mean concentration of 22 µg RE/g (range 0-98 µg RE/g) (Olson, et al., 1984). For infants aged 0-12 months (n = 133), the vitamin A concentrations ranged from 1-165 µg RE/g (Olson, et al., 1984).

Acute Toxicity

11. Vitamin A excess, known as hypervitaminosis A, can occur when large amounts of liver and/or retinol supplements are consumed, although acute adverse effects from dietary sources of vitamin A are rare (EVM, 2002). Commonly observed symptoms of acute toxicity include nausea, vomiting, lethargy, anaemia, abdominal pain, anorexia, blurred vision, irritability and headaches (Penniston and Tanumihardjo, 2006). Bulging of the fontanelles occurs in neonates and in infants (Penniston and Tanumihardjo, 2006). Acute toxicity occurs at doses in excess of 100,000 µg RE/day in adults and 10,000 µg RE/day in children (Perrotta, et al., 2003). Acute hypervitaminosis A occurs in 0-7 year olds if intake is equivalent to 90,000 – 225,000 µg RE/day, dependent on body size, weight, dietary factors and general health (Bendich and Langseth, 1989).

Chronic Toxicity

12. Chronic vitamin A toxicity is associated with chronic headache, intracranial hypertension and alopecia as well as adverse effects on the skin, bone and liver (Penniston and Tanumihardjo, 2006). Chronic hypervitaminosis A in children is generally observed after intake of >3,500 µg RE/day (Perrotta, et al., 2003). Perrota, et al., (2003) commented that hypervitaminosis A toxicity in childhood is mainly as a result of vitamin A supplement abuse rather than from ingestion of food sources

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. (Perrotta, et al., 2003). Vitamin A levels quickly return to normal range if high intake is ceased (Bendich and Langseth, 1989).

13. Twin 7 month old infants were identified as having chronic vitamin A toxicity symptoms as a result of consuming 120 g of homogenised chicken liver for four months, which led to an intake of ~12,100 µg RE/day (Allen and Haskell, 2002). Both twins developed irritability, vomiting, and bulging anterior fontanelles (Mahoney, et al., 1980). Computed tomograms (CT) of the brain showed enlarged ventricles in both infants and dilated subarachnoid spaces in one (Mahoney, et al., 1980).

14. A fatal case of vitamin A overdose has been reported, with a newborn baby accidentally receiving an aqueous solution containing approximately 27,000 µg RE/day for 11 days (Bendich and Langseth, 1989)..

15. SCF (2002) reported that the lowest doses of preformed vitamin A leading to specific adverse effects were as follows:

Bulging fontanelle 7500 µg RE (as a single dose in infants) Hepatotoxicity 7500 µg RE/day for 6 years Bone density/fracture 1500 µg RE (analyses do not show a threshold) Lipid metabolism 7500 µg RE/day for 4 years (Only a minor change) Teratogenicity >3000 µg RE/day (based on Rothman et al.,1995)

Teratogenicity

16. Retinol was identified as a teratogen in 1985 following isotretinoin, a retinoid, being prescribed for certain skin disorders (EVM, 2002). Severe malformations of the heart, thymus, face, jaw, ears, palate and brain were some of the characteristics identified in the 94 confirmed cases in the US (EVM, 2002). An elevated risk of isotretinoin-related malformations was observed if the maternal oral dose ranged between 0.5 and 1.5 mg/kg b.w./day (EVM, 2002).

17. The SCF (2002) established a tolerable upper intake level of 3000 µg RE/day for adults specifically because of the teratogenic risk in the preliminary stages of pregnancy (SCF, 2002). The 3000 µg RE/day for adults was based on the results of the Rothman et al, (1995) study, in which approximately 23,000 pregnant women answered a questionnaire aiming to identify vitamin A intake via the diet and supplements. Of the children born, 339 were classified as having a birth defect, with 121 malformations classified to be of cranial-neural-crest origin (Rothman, et al., 1995). The percentages of babies with cranial-neural-crest defects were 0.52 and 1.06 in women with intakes from food of 0-1500 µg RE/day and more than 3000 µg RE/day, respectively (SCF, 2002). The Rothman et al, (1995) study has been criticised because only 76.5% of pregnancy outcomes were assessed by physicians, with the remaining information being provided by the mother (SCF, 2002).

18. Mastroiacovo et al, (1999) collected data from 423 babies which were exposed to high doses of vitamin A (3000, 7500, 9000 and 15,000 µg RE/day) and only 3 malformations were reported. No abnormalities were observed in women whose intake exceeded 15,000 µg RE/day (Mastroiacovo, et al., 1999). The UK 4

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. Expert Group on Vitamins and Minerals (EVM) concluded that a precise threshold for any teratogenic effects is uncertain, but that it was prudent to assume it could be 3000 µg RE/day (EVM, 2002).

Tolerable Upper Intake Level

19. Table 2 shows the tolerable upper levels (ULs) for preformed vitamin A (includes retinol and retinyl esters) (µg RE/day) established by the SCF for different age groups. The UL of 3000 µg RE/day was based on the teratogenicity data of Rothman et al, (1995), but considered to be also relevant to subgroups other than pregnant women since it was 2.5-fold lower than the lowest daily intake that had been associated with hepatotoxicity during chronic intake. The ULs for infants and children were extrapolated from the 3000 µg RE/day for adults, on the basis of relative body weight and difference in basal metabolic rate (SCF, 2002). A UL for the age group below 1 year was not recommended by the SCF, however a UL of 600 µg RE/day has been established by the U.S Institute of Medicine (da Silva Ribeiro, et al., 2010).

Table 2: Tolerable upper intake levels for various age groups (SCF, 2002)

Age (years) Tolerable Upper Intake Level for preformed vitamin A (retinol and retinyl esters) (µg RE/day) 1-3 800 4-6 1100 7-10 1500 11-14 2000 15-17 2600 Adults 3000

Occurrence

Breast Milk

20. The majority of children are born with low levels of vitamin A which are increased during the first six months of life (Olson, et al., 1984). The highest concentrations of vitamin A in breast milk are found up to 10 days after birth (see table 3) (Ross and Harvey, 2003). The colostrum (0 – 3 days) is particularly rich in vitamin A compared to mature milk (Ross and Harvey, 2003). Average vitamin A levels in colostrum in developed countries is ~ 100 µg/100 ml (Underwood, 1994). The range of vitamin A levels in the breast milk of well-nourished women in Europe is 40-70 µg/100 ml, with the higher levels generally seen in women whose diet includes a higher intake of fats, particularly animal fats (Ross and Harvey, 2003).

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. Table 3: Vitamin A concentrations in breast milk at different stages of lactation. Adapted from Linkages (2001) and (Ross and Harvey, 2003)

Colostrum Transitional breast milk Mature breast milk (Child’s age: 0-3 days) (Child’s age: 3-14 days) (Child’s age: day 14- 6 months) Vitamin A levels Vitamin A levels Vitamin A levels (developed countries) (developed countries) (developed countries) Approx. 151 µg/100 ml Approx. 88 µg/100 ml Approx. 75 µg/100 ml

22. Mello-Neto et al. (2009) reported mean vitamin A concentrations in mature breast milk of 34 µg/100 ml (±SD 19.7 µg/100 ml) in a Brazilian population. They found significant positive associations between oral contraceptive use and higher levels of vitamin A in breast milk however no specific data were reported (Mello- Neto, et al., 2009).

Infant Formula

23. Infant formula typically contains a higher concentration of several micronutrients than breast milk (Bender, 2003). This is partly to account for the fact that absorption of breast milk is greater than infant formula, but also to allow for losses during storage (Bender, 2003). Major brands of infant formula contain 63 – 82 µg RE/100 ml (Leaf, 2007). In the EU, infant formula is required to contain 14-43 µg retinol equivalents per 100 kj (60-189 kcal) (Penniston and Tanumihardjo, 2006). Infant formulas are prepared to ensure adequate intake of vitamins is achieved if 150 ml/kg bw/day is consumed (Leaf, 2007).

Exposure

Exclusively breast fed

24. Based on an average vitamin A concentration of 50 µg/100 ml in breast milk, Underwood (1994) estimated vitamin A intake to be 350 and 250 µg RE/day in breast-fed infants aged 0-6 months and 6-12 months respectively. The European Food Safety Authority (EFSA) has concluded that 800 ml and 1,200 ml are reasonable estimates of average and high level consumption of breast milk or infant formula before weaning (e.g. EFSA, 2012). Based on these consumption figures and the upper end of the range of vitamin A in breast milk from mother’s from developed countries (40-70 µg RE/100 ml), vitamin A intake of exclusively breast-fed infants aged 0-6 months would be 560 and 840 µg RE/day for average and high level consumption, respectively.

Infant formula

25. For UK infant formula with a vitamin A concentration at the upper end of the reported range (63-82 µg RE/100 ml), consumption of 800 or 1200 ml/day would

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. result in intakes of 656 or 981 µg RE/day for average and high level consumption. Alternatively, based on a maximum of 180 µg/100 kcal and a minimum of 60 kcal/100 ml as stipulated in the EC Commission Directive (2006) (i.e.180 µg/167 ml, together with infant feeding instructions, the intakes at different ages could be as shown in Table 4).

Table 4: Adapted from various formula feeding instructions (circa 2003)

Approx Weight of Total Maximum Feeds Vitamin A intake age of baby (kg) quantity of Vitamin A per (µg RE/day) baby feed (ml) concentration 24 hr as stipulated by regulation (µg RE/ ml) Birth 3.5 90 1.08* 6 583.5 2 weeks 4 115 1.08* 6 745 2 months 5 170 1.08* 5 918 4 months 6.5 200 1.08* 5 1080 6 months 7.5 225 1.08* 4 972 7-12 8+ 225 1.08* 3 729 months *Based on 180 µg/167 ml, as stipulated by EC Commission Directive (2006)

26. Information on a pack of follow-on formula for infants 6-12 months specifies that it contains approximately 75 µg vitamin A per 100 ml, and that infants should be given 500-600 ml per day, therefore 600 ml will provide the 6-12 month infant with 450 µg RE/day, before taking into account consumption of solid foods.

Weaning diet

27. From a 1986 survey by the Ministry of Agriculture, Fisheries and Food (MAFF) on 488 6-12 month old infants, a mean total intake of 765 µg RE/day was estimated, of which 200 µg RE/day (approximately 34%) was from infant formula (MAFF, 1992). Significant contributions also came from milk and milk products (23%) and meat (largely liver and foods containing liver) (17%) (MAFF, 1992). The estimated daily intakes are shown in table 5 (MAFF, 1992).

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited.

Table 5: Average daily vitamin A intakes (µg RE/day) by age and sex (MAFF, 1992)

RE Males Females Infants 6-9 9-12 6-12 6-9 9-12 6-12 6-12 months months months months months months months Mean 816 711 771 784 769 759 765 Median 733 593 685 678 617 655 670 Lower 298 209 254 295 284 291 282 2.5% Upper 1757 1840 1800 1871 2653 1976 1873 2.5% SD 404 396 403 389 605 510 463 Number 130 96 226 128 134 262 488 of Infants

28. The average daily intake of vitamin A from different food types in infants aged 6-12 months are shown in table 6 (MAFF, 1992).

Table 6: Average daily intakes of vitamin A from food types for infants (aged 6- 12 months) who received supplements and those who did not (MAFF, 1992)

Food Types Vitamin A (µg RE) With supplements Without supplements Commercial baby food 104 88 Breast milk 32 25 Infant formulas 174 227 Cows' milk 150 126 Family foods 309 296

29. For 6-9 month olds, those taking a multivitamin supplement (47% of the group) received on average an additional 165 µg RE to total intake, which equalled an estimated average intake of 933 µg RE (MAFF, 1992). For 9-12 month olds, those taking a multivitamin supplement (40% of group) received on average an additional 168 µg RE to total intake, which equalled an estimated average intake of 936 µg RE (MAFF, 1992).

30. There are numerous multivitamin supplements on the UK market that are marketed for pre-term infants and infants aged 0-12 months. The vitamin A content provided from a recommended daily dose of listed multivitamin supplements are as follows: (200 µg RE, 233 µg RE and 757 µg RE (Leaf, 2007). Leaf (2007) noted that it is recommended to double the 200 µg RE dose if it is prescribed to pre-term infants (Leaf, 2007).

31. The Feeding Infants and Toddlers Study (FITS) 2002 survey recorded the food intake of 3,022 U.S. infant and toddlers (aged 4-24 months) over a 24 hour period in order to determine the intake of nutrients and energy, including vitamin A

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. (Fox, et al., 2006). Briefel et al., (2006) assessed the results of the FITS 2002 study for the use of dietary supplements in 4 to 24 month old infants. 8% and 19% of infants aged 4-5 months and 6-11 months received some type of dietary supplement, respectively. The median and 90th percentile of vitamin A intake in 6-11 month old supplement users were 1,053 and 1,451 µg RE/day, respectively, which was an additional 367 and 480 µg RE/day in comparison to the median and 90th percentile vitamin A intake in non-users (Table 7).

32. The FITS 2008 surveyed usual nutrient intake in 3,273 US infants and toddlers aged 0-47 months. Table 7 compares vitamin A intake distributions between infants aged 0-5 months and 6-11 months. It was calculated that 26% of infants aged 6 to 11 months (n=505) exceeded the UL for vitamin A of 600 µg RE/day from food, beverages and supplements whereas 16% exceeded the UL from only food and beverages (Butte, et al., 2010). In the survey, 8.8% and 12.6% of infants aged 0-5 months and 6-11 months, respectively, received vitamin A supplementation (Butte, et al., 2010). Similarly, in the US 1999-2002 National Health and Nutrition Examination Survey (NHANES) 8.8% of infants aged 0-11 months (n=1040) received vitamin A supplementation (Picciano, et al., 2007). In comparison to the FITS 2002 survey, infant supplementation had decreased by 6.4% in infants aged 6 to 11 months.

Table 7: Estimates of vitamin A intake of food and beverages (with or without supplementation) from the FITS (2002) and (2008) surveys in the US. Adapted from Briefel et al, (2006) and Butte et al, (2010)

Age Numbers Supplement Median Mean ± 90th (Months) user intake Standard intake percentile Deviation (µg percentile (µg RE/day) RE/day) (µg RE/day) 0 – 5 382 Y 491 582 ± 18.2 815 (Butte et al, 2010) 6 -11 505 Y 720 744 ± 8.2 987 (Butte et al, 2010) 6 – 11 187 Y 1,053 1,083 ± 21.4 1,451 (Briefel et al, 2006) 6 – 11 1.208 N 686 707 ± 5.6 671 (Briefel et al, 2006)

33. The actual intakes of vitamin A amongst infants aged 6-11 months may have been lower than those calculated because infants may spill the solids/liquids that are being given to them to consume. Younger infants are also prone to being sick after feeding which could lower actual intake at this age group.

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. Predictions for high level intakes from liver

34. It is currently advised by the Department of Health (DH) that mashed and soft food start to be introduced at 6 months of age whilst also continuing to consume the recommended amounts of infant formula or follow-on formula (DH, 2012). From 6 months, cooked vegetables (such as parsnip, potato, sweet potato or carrot), mashed banana, avocado, pear or cooked apple are recommended as suitable weaning foods (DH, 2012). Once the infant is comfortable, the infant can be offered different foods such as meat, fish, pasta, noodles, bread, chapatti, lentils, mashed rice, low sugar dairy products like cheese, yoghurt and fromage frais (DH, 2012). By 8-9 months, the infant should be eating a wide variety of soft foods, and by 10-12 months, chopped food can be introduced (DH, 2012).

35. Mashed carrot is a popular choice for 6-12 month olds, which made up 10% relative contribution to total RE intake in the 2002 FITS survey of US infants (Fox et al, 2006). Based on this, 10% of a total intake of 987 (90th intake percentile for 6-12 month old infants, Butte et al, 2010) would give an intake of vitamin A intake from carrot consumption at approximately 98 µg RE/day.

36. Liver consumption is not completely discouraged above the age of 6 months. Consumption data are not available for UK infants. An iron rich meal containing 125 g of chicken liver is listed on a homemade baby food recipe website (Homemade baby food recipes 20121). It is mixed with 125 g of mince, 250 g of butternut squash and 250 ml of chicken stock and blended into a puree for the infant. In addition to the chicken liver, the other ingredients also contain a proportion of vitamin A. A typical jar of infant food is approximately 125 g. Assuming that 125 g is a typical portion size for an infant meal, a serving of this recipe would contain about 20 g of chicken liver, which would contain about 800 µg RE. Average vitamin A content of chicken liver is about 40 µg RE/g and so this recipe could provide about 5000 µg RE/day from the chicken liver alone. If this is consumed over the course of a week, averaged intake from this source would be in the region of 720 µg RE/day, before taking into account other dietary sources.

Risk characterisation

37. Estimates of vitamin A intake by exclusively breast-fed infants are in the region of 560 and 840 µg RE/day for average and high level consumption. Exclusively formula-fed infants could have slightly higher levels, in the region of 1000 µg RE/day.

38. Estimates of vitamin A intake for UK infants following introduction of solid foods are based on data from the 1980s and it is unclear whether they would be representative of current intake. Nevertheless they indicate mean and high level intakes in the region of 800 and 1900 µg RE/day, respectively. These data are supported by more recent data from the USA.

1 http://www.homemade‐baby‐food‐recipes.com/baby‐dinner‐recipes.html 10

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited.

39. Thus exposure of some infants exceeds the tolerable upper level of 800 µg RE/day, established by the SCF for children aged 1-3 years. Use of dietary supplements or consumption of foods containing liver have the potential to further increase the intakes.

Questions for the Committee

40. Members are invited to comment on the information provided in this paper and to consider the following questions.

i). Do Members consider the estimates of vitamin A intake in a) breast milk, b) formula and c) dietary sources indicate a concern for the health of infants ii) Do Members consider that the current advice (that liver should be avoided before 6 months and not consumed more than once a week by older infants) is appropriate? iii) Do Members have recommendations for additional information that should be obtained in order to reach conclusions?

Secretariat April 2012

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. References

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This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. TOX/2012/16 ANNEX A

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

Review of potential risks from high levels of vitamin A in infant nutrition

Abbreviations COMA Committee on Medical Aspects of Food Policy CT Computed Tomograms DH Department of Health DRV Dietary Reference Values EVM The UK Expert Group on Vitamins and Minerals FAO Food and Agriculture Organization of the United Nations FITS Feeding Infants and Toddlers Study IU International Unit MAFF Ministry of Agriculture, Fisheries and Food NHANES National Health and Nutrition Examination Survey RDA Recommended Daily Allowance RE Retinol Equivalent RNI Reference Nutrient Intake SACN Scientific Advisory Committee on Nutrition UL Upper Level WHO World Health Organization of the United Nations

Search Strategy

General Vitamin A exposure search Databases interrogated – • EFSA • COT • FSA

Scientific publications literature search

Specific search terms:

Vitamin A AND breast milk Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable. Exclusion Criteria – • Supplementation research in undeveloped countries • Supplementation programs in undeveloped countries • Deficiency related research

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. Vitamin A AND infant formula Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable. Exclusion Criteria – • Supplementation studies in undeveloped countries • Supplementation programs in undeveloped countries • Infant formulas in non-EU countries

Vitamin A AND hypervitaminosis Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable. Exclusion Criteria – • Supplementation studies in undeveloped countries • Supplementation programs in undeveloped countries • Hypervitaminosis in adults

Vitamin A AND infant diet Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable. Exclusion Criteria – • Supplementation studies in undeveloped countries • Supplementation programs in undeveloped countries • Infant diet in undeveloped countries • Children’s diet (above >2 years) in developed countries

Vitamin A AND weaning Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable. Exclusion Criteria – • Supplementation studies in undeveloped countries • Supplementation programs in undeveloped countries • Infant weaning in undeveloped countries • Children’s diet (above >2 years) in developed countries

Retinol AND exposure Search Dates (From/To) - From January 2002 to present* *Some papers pre-2002 were included if it felt they added value to the paper, particularly with regards to papers which identified previous cases of chronic and acute vitamin A toxicity and where a dose which lead to toxicity was identifiable.

This is a background paper for discussion. It does not reflect the views of the Committee and should not be cited. Exclusion Criteria – • Supplementation studies in undeveloped countries • Supplementation programs in undeveloped countries • Adult retinol exposure • Deficiency related research

The above mentioned search terms were also used in google. It identified latest government advice and opinions.