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Scientific opinion on the tolerable upper intake level for selenium

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

Abstract

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for selenium. Systematic reviews of the literature were conducted to identify evidence regarding excess selenium intake and clinical effects and potential biomarkers of effect, risk of chronic diseases and impaired neuropsychological development in humans. Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, is selected as the critical endpoint on which to base a UL for selenium. A lowest-observed-adverse-effect-level (LOAEL) of 330 μg/day is identified from a large randomised controlled trial in humans (the Selenium and Vitamin E Cancer Prevention Trial (SELECT)), to which an uncertainty factor of 1.3 is applied. A UL of 255 μg/day is established for adult men and women (including pregnant and lactating women). ULs for children are derived from the UL for adults using allometric scaling (body weight0.75). Based on available intake data, adult consumers are unlikely to exceed the UL, except for regular users of food supplements containing high daily doses of selenium or regular consumers of Brazil nuts. No risk has been reported with the current levels of selenium intake in European countries from food (excluding food supplements) in toddlers and children, and selenium intake arising from the natural content of foods does not raise reasons for concern. Selenium-containing supplements in toddlers and children should be used with caution, based on individual needs.

Keywords: UL; dietary reference value; selenium; tolerable upper intake level.

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Figures

Figure 1
Figure 1
Stepwise approach for evidence integration and uncertainty analysis applied to sQ2, by study design

  1. BoE: body of evidence; LoE: line of evidence.

Figure 2
Figure 2
Approach applied to assign the final level of certainty in a causal relationship

  1. Adapted from OHAT‐NTP (2019).

    LoE: line of evidence; PC: prospective cohort study; HCT: human controlled trial; RoB: risk of bias.

    (a): As an example, a ‘high level of certainty’ means that, based on the available evidence, experts are 75%–100% certain that selenium is positively and causally associated with the disease of interest.

Figure 3
Figure 3
Schematic representation of selenium metabolism

  1. Based on Burk and Hill (2015), Combs (2015), Saito (2021), Jäger et al. (2016a,b), Thiry et al. (2012), and Rayman et al. (2008a).

    DMSe: dimethylselenide; γ‐Glu‐MeSeCys: γ‐glutamyl‐Se‐methyl‐selenocysteine; INMT: indolethylamine N‐methyltransferase; MeSeCys: Se‐methyl‐selenocysteine; SeMet: selenomethionine; SeCys: selenocysteine; TMSe: trimethylselenonium ion; tRNA: transfer ribonucleic acid; TPMT: thiopurine S‐methlytransferase.

Figure 4
Figure 4
Dose–response meta‐analysis on the relationship between mean selenium intakes and mean selenium plasma concentrations. At 70 μg/day one knot was identified from the best fitting linear splines model and coefficients estimated below and above such a cut‐off (β1 = 1.25, β2 = 0.43, α = 23.10)

  1. Se: selenium.

Figure 5
Figure 5
Distribution of selenium‐containing supplements available in EU Member States and Norway according to the recommended daily dose displayed on labels

  1. Source: Mintel GNPD database. Search for selenium‐containing supplements available in the EU market in the last 5 years (from January 2016 to December 2021). A total of 1,238 products available in 24 EU Member States and Norway were identified.

Figure 6
Figure 6
Mean, median, 5th and 95th percentiles of selenium intakes in infants (< 1 year old), toddlers (≥ 1 year to < 3 years old), other children (≥ 3 years to < 10 years old) and adolescents (≥ 10 years to < 18 years old), by sex and country

  1. 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.

    DE: Germany; FI: Finland; FR: France; IT: Italy; LV: Latvia; NL: Netherlands.

    Source: (EFSA NDA Panel, 2014), except for infants.

Figure 7
Figure 7
Mean, median, 5th and 95th percentiles of selenium intakes in adults (≥ 18 years to < 65 years old) and older adults (≥ 65 years), by sex and country

  1. 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.

    FI: Finland; FR: France; IE: Ireland; IT: Italy; LV: Latvia; NL: Netherlands; SE: Sweden.

    Source: (EFSA NDA Panel, 2014).

Figure 8
Figure 8
Observational studies investigating the effect of selenium on the incidence of hypertension

  1. *Denotes hypertension definition different from other studies.

    BD: Bangladesh; BE: Belgium; BEST Bangladesh Vitamin E and Selenium Trial; B‐Se: blood selenium; CI: confidence interval; CN: China; FLEMENGHO: Flemish Study on Environment Genes and Health Outcomes; FM: females and males; N‐Se: nail selenium; NR: not reported; P/S‐Se: plasma/serum selenium, Q: quantile; SD: standard deviation; y: years.

Figure 9
Figure 9
Observational studies investigating the effect of selenium on continuous measures of blood pressure

  1. *Denotes estimated annual changes in blood pressure; **denotes mother–child pair studies where exposure was analysed in the mothers and outcome in their child; the age of children is shown.

    BD: Bangladesh; BP: blood pressure; B‐Se: blood selenium; CI: confidence interval; FM: females and males; GR: Greece; MX: Mexico; SD: standard deviation; U‐Se: urinary selenium; ZA: South Africa; y: years.

Figure 10
Figure 10
Intervention studies investigating the effects of selenium supplementation vs placebo on thyroid hormone concentrations (standardised mean differences), sorted by study duration

  1. *Denotes depletion study.

    BR: Brazil; CI: confidence interval; DK: Denmark; FM: females and males; IT: Italy; N: number; NR: not reported; NZ: New Zealand; PRECISE: PREvention of Cancer by Intervention with Selenium SD: standard deviation; Suppl‐I: inorganic selenium supplement; Suppl‐O: organic selenium supplement; T3: triiodothyronine; T4: thyroxine; TSH: thyroid‐stimulating hormone, UK: United Kingdom.

Figure 11
Figure 11
Intervention studies investigating the effects of selenium supplementation vs placebo on incidence of prostate cancer, sorted by supplemental dose

  1. CI: confidence interval; duration: duration of the intervention and follow‐up phase for studies with an observational period (i.e. Klein et al., 2011); FUP: follow‐up; GN: highest dose group from each study; HR: hazard ratio; M: males; NBT: Negative Biopsy Trial; NPC: Nutritional Prevention of Cancer; NZ: New Zealand; PR: Porto Rico; RCT: randomised controlled trial; SD: standard deviation; SELECT: Selenium and Vitamin E Cancer Prevention Trial; Suppl‐O: organic selenium supplement; SWOG: Southwest Oncology Group; US: United States; y: years.

    Notes: For Algotar et al. (2013b), HR adjusted for age at baseline, race, baseline PSA, and baseline plasma Se concentration; for Duffield‐Lillico et al. (2003a), HR adjusted for age and smoking.

Figure 12
Figure 12
Observational studies on plasma/serum selenium concentrations and incidence of prostate cancer

  1. *Denotes imputed standard error.CI: confidence interval; CA: Canada; CARET: Carotene and Retinol Efficacy Trial; DE: Germany; DK: Denmark; EPIC: European Prospective Investigation into Cancer and Nutrition; ES: Spain; FI: Finland; GR: Greece; IT: Italy; M: males; MCHES: Mobile Clinic Health Examination Survey; N: number; NL: The Netherlands; N: number NR: not reported; OR: odds ratio; P/S‐Se: plasma/serum Se; Q: quantile; RR: risk ratio; SD: standard deviation; SE: Sweden; UK: United Kingdom; ULSAM: Uppsala Longitudinal Study of Adult Men; US: United States; y: years.

Figure 13
Figure 13
Observational studies on measures of selenium intake other than plasma/serum selenium and incidence of prostate cancer

  1. ATBC: Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention; C: category; CA: Canada; CI: confidence interval; d: day; DK: Denmark; FI: Finland; HPFS: Health Professionals Follow‐Up Study; M: males; MEC: Multiethnic Cohort; N: number; NL: Netherlands; N‐Se: nail selenium; NR: not reported; OR: odds ratio; P/S‐Se: plasma/serum selenium; PCPT: Prostate Cancer Prevention Trial; Q: quantile; RR: risk ratio; SFFQ: semiquantitative food frequency questionnaire; Suppl‐Q: supplement use questionnaire; US: United States, y: years.Note: For Kristal et al.,  stratified results plotted for incidence of prostate cancer for Gleason scores 2–7 (stratified results for Gleason scores 8–10 available in evidence table in Appendix D.7.2).

Figure 14
Figure 14
Intervention studies investigating the effect of selenium supplementation vs placebo on incidence of skin cancer, sorted by duration

  1. *Denotes estimated risk ratios and standard errors; **denotes incidence rates instead of N events.BCC: basal cell carcinoma; CI: confidence interval; FM: females and males; GN: highest dose group from each study; HR: hazard ratio; N: number; NBT: Negative Biopsy Trial; NPC: Nutritional Prevention of Cancer; NZ: New Zealand; SCC: squamous cell carcinoma; SD: standard deviation; Sel/Cel: Selenium and Celecoxib; Suppl‐O: organic Se supplement; US: United States: y: years.Note: Participants in the NPC trial were at high risk of non‐melanoma skin cancer at baseline having been diagnosed with 1 or more SCC or 2 or more BCC within the year prior to randomization.

Figure 15
Figure 15
Observational studies on selenium exposure and incidence of skin cancer

  1. *Denotes imputed standard error.AU: Australia; BCC: basal cell carcinoma; C: category; CI: confidence interval; d: day; FI: Finland; FM: females and males; HPFS: Health Professionals Follow‐Up Study; MCHES: Mobile Clinic Health Examination Survey; N: number; NCC: nested case–control study; NHS: Nurses' Health Study; NR: not reported; NSC: Nambour Skin Cancer; N‐Se: nail selenium; OR: odds ratio; P/S‐Se: plasma/serum selenium; Q: quantile; RR: risk ratio; SD: standard deviation; SCC: squamous cell carcinoma; SCP: Skin Cancer Prevention; SFFQ: semiquantitative food frequency questionnaire; Suppl‐Q: supplement use questionnaire; UK: United Kingdom: VITAL: VITamins And Lifestyle.Notes: Knekt et al. (1991) and Karagas et al. (1997) are NCCs; Karagas et al. (1997) enrolled participants with at least one BCC or SCC cancer previously removed.

Figure 16
Figure 16
Intervention studies investigating the effect of selenium supplementation vs placebo on the incidence of T2DM

  1. *Denotes estimated risk ratios and standard errors.CA: Canada; CI: confidence interval; d: day; FM: females and males; G: group; HR: hazard ratio; N: number; PR: Puerto Rico; SD: standard deviation; Suppl‐O: organic selenium supplement; US: United States; y: years.Note: In Karp et al. (2013): the ratio of participants assigned to G1 and G2 was 1:2: i.e. 521 individuals in the control group and 1:040 individuals in treatment group.

Figure 17
Figure 17
Intervention studies investigating the effect of selenium supplementation vs placebo on fasting glucose

  1. CI: confidence interval; d: day; ES: Spain; FM: females and males; IR: Iran; N: number; NR: not reported; SD: standard deviation; Se: selenium; Suppl‐O: organic selenium supplement; US: United States; wks: weeks.Notes: Baseline selenium intake estimated with six 24‐h recalls in Hosseinzadeh et al. (2016) (in μg/day). Baseline selenium measured in whole blood in Navas‐Carretero et al. (2011) (in μg/L).

Figure 18
Figure 18
Intervention studies investigating the effect of selenium supplementation vs placebo on fasting insulin

  1. CI: confidence interval; d: day; ES: Spain; FM: females and males; IR: Iran; N: number; NR: not reported; SD: standard deviation; Se: selenium; Suppl‐O: organic selenium supplement; wks: weeks.Notes: Baseline selenium intake estimated with six 24‐h recalls in Hosseinzadeh et al. (2016) (in μg/day). Baseline selenium measured in whole blood in Navas‐Carretero et al. (2011) (in μg/L).

Figure 19
Figure 19
Intervention studies investigating the effect of selenium supplementation vs placebo on fasting glucose and fasting insulin, excluding: Karamali et al. (2015), Mesdaghinia et al. (2017), Raygan et al. (2018), Tamtaji et al. (2019) and Jamilian et al. (2015)

  1. CI: confidence interval; d: day; ES: Spain; FM: females and males; IR: Iran; N: number; NR: not reported; SD: standard deviation; Se: selenium; Suppl‐O: organic selenium supplement; US: United States; wks: weeks.Notes: Baseline selenium intake estimated with six 24‐h recalls in Hosseinzadeh et al. (2016) (in μg/day). Baseline selenium measured in whole blood in Navas‐Carretero et al. (2011) (in μg/L).

Figure 20
Figure 20
Funnel plot of the RCTs on incidence of T2DM
Figure 21
Figure 21
Observational studies on selenium exposure and incidence of T2DM, most adjusted RRs from PCs and NCCs

  1. C: category: CI: confidence interval; CN: China; d: day; DE: Germany; EPIC: European Prospective Investigation into Cancer and Nutrition; ES: Spain; IT: Italy; N: number; NR: not reported; FM: females and males; SD: standard deviation; SE: Sweden; OR: Odds Ratio; ORDET: HORmones and Diet in the ETioliogy of Breast Cancer; P/S‐Se: plasma/serum selenium; Q: quantile; ref: reference; SFFQ: semiquantitative food frequency questionnaire; T‐Se: toenail selenium; ULSAM: Uppsala Longitudinal Study of Adult Men; US: United States; y: years.Note: For Stranges et al., : N analysed refers to total number of participants.

Figure 22
Figure 22
Observational studies on selenium exposure and incidence of T2DM, most adjusted highest vs lowest RRs from PCs and NCCs

  1. C: category; CI: confidence interval; CN: China; d: day; DE: Germany; EPIC: European Prospective Investigation into Cancer and Nutrition; ES: Spain; FM: females and males; IT: Italy; N: number; NR: not reported; ORDET: HORmones and Diet in the ETioliogy of Breast Cancer; P/S‐Se: plasma/serum selenium; SD: standard deviation; SE: Sweden; SFFQ: food frequency questionnaire; T‐Se: toenail selenium; OR: Odds Ratio; ULSAM: Uppsala Longitudinal Study of Adult Men; US: United States: y: years.Note: For Stranges et al., : N analysed refers to total number of participants.

Figure 23
Figure 23
Funnel plot of the observational studies on incidence of T2DM included in the dose–response analysis
Figure 24
Figure 24
Intervention studies investigating the effect of selenium supplementation vs placebo on all‐cause mortality, sorted by supplemental dose

  1. *Denotes estimated risk ratio and standard error.CI: confidence interval; d: day; duration: duration of the intervention and follow‐up phase for studies with an observational period (i.e. Klein et al., ; Rayman et al., 2018); DK: Denmark; FM: females and males; FUP: follow‐up; GN: highest dose group from each study; HR: hazard ratio; NBT: Negative Biopsy Trial; NZ: New Zealand; PR: Puerto Rico; PRECISE: PREvention of Cancer by Intervention with Selenium; RCT: randomised controlled trial; SD: standard deviation; Se: selenium; SELECT: Selenium and Vitamin E Cancer Prevention Trial; Suppl‐O: organic selenium supplements; SWOG: Southwest Oncology Group; US: United States; y: years.

Figure 25
Figure 25
Observational studies on plasma/serum selenium and all‐cause mortality

  1. *Denotes Q1 vs Q2‐Q3‐Q4.

    C: category; CI: confidence interval; CN: China; ES: Spain; EVA: Étude du Vieillissement Artériel; FI: Finland; FM: females and males; FR: France; ilSIRENTE: Invecchiamento e Longevità nel Sirente; InCHIANTI: Invecchiare in Chianti; IT: Italy; N: number; NHANES: National Health and Nutrition Examination Survey; NR: not reported; P/S‐Se: plasma/serum selenium; Q: quantile; ref: reference; RR: risk ratio; SD: standard deviation; SE: Sweden; Se: selenium; SES: cohort in the south‐east of Sweden; UK: United Kingdom; US: United States; WHAS: Women's Health and Aging Studies; y: years.

Figure 26
Figure 26
Observational studies on measures of selenium exposure other than plasma/serum selenium and all‐cause mortality

  1. C: category; CI: confidence interval; CN: China; d: day; ES: Spain; FM: females and males; IT: Italy; MPP: Malmö Preventive Project; N: number; NR: not reported; PREDIMED: Prevención con Dieta Mediterránea; Q: quantile; ref: reference; RR: risk ratio; SD: standard deviation; SE: Sweden; SeP: selenoprotein P; SFFQ: semiquantitative food frequency questionnaire; SWHS: Shanghai Women's Health; SMHS: Shanghai Men's Health study; y: years.

None
Figure B.1: Flow chart for the selection of studies addressing sQ1

  1. Note: 26 articles identified from the search for sQ1 were included in the dose–response plasma‐intake modelling.

None
Figure B.2: Flow chart for the selection of studies addressing sQ2

  1. Note: 17 studies identified through the search addressing sQ2 were included in the dose–response analysis for plasma‐intake.

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