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Scientific opinion on the tolerable upper intake level for preformed vitamin A and β-carotene - PubMed

  • ️Mon Jan 01 2024

Scientific opinion on the tolerable upper intake level for preformed vitamin A and β-carotene

EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) et al. EFSA J. 2024.

Abstract

Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β-carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β-carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child-bearing age, pregnant and lactating women and post-menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4-11 months) and 2600 μg RE/day (adolescents 15-17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β-carotene. The available data were not sufficient and suitable to characterise a dose-response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β-carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β-carotene. The use of supplemental β-carotene by the general population should be limited to the purpose of meeting vitamin A requirements.

Keywords: adverse health effects; lung cancer; retinol; teratogenicity; tolerable upper intake level; vitamin A; β‐Carotene.

© 2024 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.

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Conflict of interest statement

If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu.

Figures

FIGURE 1
FIGURE 1

Chemical structure of different forms of vitamin A: (A) All‐trans‐retinol; (B) All‐trans‐retinyl ester (retinyl acetate); (C) All‐trans‐retinoic acid; (D) All‐trans‐β‐carotene. Source: PubChem.

FIGURE 2
FIGURE 2

Distribution of preformed vitamin A content in food supplements as displayed on labels of products in EU Member States and Norway (μg RE per serving). Source: Mintel GNPD. Search for vitamin A‐containing supplements available in the EU market from November 2017 to November 2022. Database refined to include only supplements with preformed vitamin A and not provitamin A carotenoids.

FIGURE 3
FIGURE 3

Preformed vitamin A and congenital birth defects. BD, birth defect; D + S, diet and supplements; FC, fortified cereals; NCCD, neural crest cell defects; NRA, normally related arteries; NTD, neural tube defects; OFC, oral facial clefts; OTD, outflow tract defects; S, supplements; TGA, transposition of great arteries.

FIGURE 4
FIGURE 4

Preformed vitamin A (μg RE/day) and risk of hip fractures. C, fixed categories; D, diet; F, females; HR, hazard ratio; IWHS, Iowa Women's Health Study; M, males; NHS, Nurses' Health Study; OR, odds ratio; PC, prospective cohort; Q, quantiles; RoB, risk of bias; RR, relative risk; S, supplements; SMC, Swedish Mammography Cohort; WHIOS, Women's Health Initiative Observational Study. Study duration represents either mean, median or maximum follow‐up. 1The intake was adjusted for energy using the residual method before categorisation; 2Numbers per category were estimated from the total sample assuming equal distribution of participants per category; 3The total number of study participants is reported instead of N per category.

FIGURE 5
FIGURE 5

Total vitamin A (μg RE/day) and risk of hip fractures. D, diet; HR, hazard ratio; F, females; IWHS, Iowa Women's Health Study; NHS, Nurse's Health Study; PC, prospective cohort; Q, quantiles; RoB, Risk of Bias; RR, relative risk; S, supplements; WHIOS, Women's Health Initiative Observational Study. Study duration represents either mean, median or maximum follow‐up. 1The intake was adjusted for energy using the residual method before categorisation; 2 Numbers per category were estimated from the total sample assuming equal distribution of participants per category.

FIGURE 6
FIGURE 6

Preformed vitamin A (μg RE/day) and risk of any fracture. C, fixed categories; D, diet; HR, hazard ratio; IRR, incidence risk ratio; F, females; IWHS, Iowa Women's Health Study; NCC, nested case‐cohort; NR, Not reported; M, males; OR, odds ratio; PC, prospective cohort; Q, quantiles; RoB, Risk of Bias; RR, relative risk; RS, Rotterdam Study; S, supplements; SMC, Swedish Mammography Cohort; ULSAM, Uppsala Longitudinal Study of Adult Men; WHIOS, Women's Health Initiative Observational Study. Study duration represents either mean, median or maximum follow‐up. 1The intake was adjusted for energy using the residual method before categorisation; 2Information was obtained from the study authors; 3The age of study participants at the time of intake assessment was estimated from the age at recruitment.

FIGURE 7
FIGURE 7

Total vitamin A (μg RE/day) and risk of any fracture. D, diet; F, females; HR, hazard ratio; IWHS, Iowa Women's Health Study; M, males; PC, prospective cohort; Q, quantiles; RR, relative risk; RS, Rotterdam Study; S, supplements; WHIOS, Women's Health Initiative Observational Study. Study duration represents either mean, median or maximum follow‐up. 1Intake adjusted for energy before categorisation; 2 Information was obtained from the study authors.

FIGURE A.1
FIGURE A.1

Flow chart for the selection of studies on teratogenicity.

FIGURE A.2
FIGURE A.2

Flow chart for the selection of studies on hepatotoxicity.

FIGURE A.3
FIGURE A.3

Flow chart for the selection of studies on bone health.

None

FIGURE E.1 Background diet intake estimates for preformed vitamin A, including offal consumption scenarios, for infants and toddlers, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to medians, and triangles and circles to P95 offal consumption scenarios of once per month and once per week, respectively. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. BE, Belgium; BG, Bulgaria; CY, Cyprus; DE, Germany; DK, Denmark; EE, Estonia; ES, Spain; FI, Finland; FR, France; HU, Hungary; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; SI, Slovenia.

None

FIGURE E.2 Background diet intake estimates for preformed vitamin A, including offal consumption scenarios, for young and older children, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to medians, and triangles and circles to P95 offal consumption scenarios of once per month and once per week, respectively. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; BG, Bulgaria; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; SE, Sweden.

None

FIGURE E.3 Background diet intake estimates for preformed vitamin A, including offal consumption scenarios, for young and older adolescents, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to medians, and triangles and circles to P95 offal consumption scenarios of once per month and once per week, respectively. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; RO, Romania; SE, Sweden; SI, Slovenia.

None

FIGURE E.4 Background diet intake estimates for preformed vitamin A, including offal consumption scenarios, for adults and older adults, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to medians, and triangles and circles to P95 offal consumption scenarios of once per month and once per week, respectively. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IE, Ireland; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; RO, Romania; SE, Sweden; SI, Slovenia.

None

FIGURE E.5 Background diet intake estimates for β‐carotene (mg/day) for infants and toddlers, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to means and triangles to medians. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. BE, Belgium; BG, Bulgaria; CY, Cyprus; DE, Germany; DK, Denmark; EE, Estonia; ES, Spain; FI, Finland; FR, France; HU, Hungary; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; SI, Slovenia.

None

FIGURE E.6 Background diet intake estimates for β‐carotene (mg/day) for younger and older children, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to means and triangles to medians. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; BG, Bulgaria; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IE, Ireland; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; RO, Romania; SE, Sweden; SI, Slovenia.

None

FIGURE E.7 Background diet intake estimates for β‐carotene (mg/day) for young and older adolescents, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to means and triangles to medians. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IE, Ireland; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; RO, Romania; SE, Sweden; SI, Slovenia.

None

FIGURE E.8 Background diet intake estimates for β‐carotene (mg/day) for adults and older adults, by sex and country. Estimates for females in orange and for males in blue. Squares correspond to means and triangles to medians. Lines represent the range between the 5th and 95th percentiles. Estimated intakes from 5th and 95th percentiles are not presented when sample size is below 60 participants. Countries for which more than one survey was available, estimates presented in the plot are those of the most recent survey; when surveys covered the same period those with the highest number of participants are displayed. AT, Austria; BE, Belgium; CY, Cyprus; CZ, Czech Republic; DE, Germany; DK, Denmark; EE, Estonia; EL, Greece; ES, Spain; FI, Finland; FR, France; HU, Hungary; IE, Ireland; IT, Italy; LV, Latvia; NL, the Netherlands; PT, Portugal; RO, Romania; SE, Sweden; SI, Slovenia.

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