Scientific opinion on the tolerable upper intake level for selenium

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. 2023 Jan 20;21(1):e07704. doi: 10.2903/j.efsa.2023.7704

Reference Study Country	Design N randomised/completed Duration^(a) Recruitment criteria	Subject characteristics at baseline^(b)	Intervention^(b)	Outcomes assessed	Results
Lippman et al. (2009) SELECT USA, Canada, and Puerto Rico	RCT G1, placebo: 8,856/8,696 G2, 200 μg Se/d: 8,910/8,752 Duration (median (min‐max)): 5.46 (4.17–7.33) yr Aged ≥ 50 yr (African American men) or ≥ 55 yr (all other men); serum prostate‐specific antigen level ≤ 4 ng/mL; DRE not suspicious for prostate cancer	Sex: M Age (yr, median (IQR)) G1: 62.6 (58.1–67.8) G2: 62.6 (58.2–68.0) BMI (kg/m ² ): NR Ethnicity (Caucasian, %) G1: 79 G2: 79 Serum Se (μg/L, median (IQR)) G1: 137.6 (124.7–151.8) G2: 135.0 (123.4–145.9) Se intake: NR	L‐selenomethionine (200 μg Se/d) vs placebo Adherence, pill counts (%) G1: 85% at yr 1; 69% at yr 5 G2: 84% at yr 1; 69% at yr 5 Serum Se at 4 yr follow up, μg/L (median (IQR)) G1: 140.1 (124.3–150.8) G2: 251.6 (218.7–275.0)	Adverse events self‐reported every 6 months during study site visit (or phone call): alopecia, dermatitis, halitosis, nail changes, fatigue, nausea. NCI Common Toxicity Criteria used for alopecia, nail changes, fatigue, and nausea. Halitosis and dermatitis defined in study protocol.	RR for adverse events (99% CI) Alopecia: 1.28 (1.01, 1.62) Dermatitis grade 1–2: 1.17 (1.00, 1.35) Dermatitis grade 3–4: 1.74 (0.56, 5.44) Halitosis: 1.17 (0.99, 1.38) Nail changes: 1.04 (0.94, 1.16) Fatigue grade 1–2: 1.09 (0.95, 1.26) Fatigue grade 3–4: 0.87 (0.40, 1.88) Nausea grade 1–2: 1.19 (0.94, 1.52) Nausea grade 3: 0.99 (0.30, 3.34) Grade 1 = mild, 2 = moderate, 3 = severe, 4 = life‐threatening.
Algotar et al. (2013b) NBT USA and New Zealand	RCT G1, placebo: 232/0 G2, 200 μg Se/d: 234/0 G2, 400 μg Se/d: 233/0 Duration (median): 35 mo High risk of prostate cancer, as evidenced by PSA > 4 ng/mL and/or suspicious digital rectal examination and/or PSA velocity (rate of PSA change over time) > 0.75 ng/mL per year; undergone a prostate biopsy negative for cancer within 12 mo of enrolment.	Sex: M Age (yr) G1: 65.5 ± 7.4 G2: 65.2 ± 8.0 G3: 65.5 ± 7.7 BMI (kg/m ² ): NR Ethnicity (Caucasian, %) G1: 84.2 G2: 83.7 G3: 82.6 Plasma Se (μg/L) G1: 124.5 ± 24.7 G2: 126.6 ± 26.9 G3: 127.2 ± 24.8 Se intake: NR	Selenised yeast (200 μg Se/d or 400 μg Se/d or) vs placebo Adherence, pill counts (%) G1: 92.1 G2: 93.2 G3: 91.2	Adverse events self‐reported to study staff every 6 months during study visit: Brittle nail and hair, garlic breath, liver/kidney abnormality (criteria NR)	N (%) adverse events Brittle nail and hair: G1: 26 (11.2) G2: 24 (10.3) G3: 20 (8.6) p = 0.63 Garlic breath, liver/kidney abnormality: G1: 14 (6.0) G2: 13 (5.6) G3: 11 (4.7) p = 0.82
Winther et al. (2015) DK PRECISE Denmark	RCT G1, placebo: 126/90 G2, 100 μg Se/d: 124/91 G3, 200 μg Se/d: 122/90 G4, 300 μg Se/d: 119/90 Duration (max): 5 yr Aged 60–74 yr; taking > 80% pills in the run‐in phase; SWOG performance status score ≤ 1; no active liver or kidney disease; no previous diagnosis of cancer (excluding NMSC); no diagnosed HIV infection; not receiving immunosuppressive therapy; not receiving ≥ 50 mg/day of Se supplements in the previous 6 mo	Sex (% F): 48.1% Age (yr): 66.1 ± 4.1 BMI (kg/m ² ): NR Ethnicity: Caucasian Plasma Se (ng/g, median (IQR)) G1: 85 (20) G2: 86 (18) G3: 88 (22) G4: 84 (19) Se intake: NR	Se‐enriched yeast (100 μg Se/d or 200 μg Se/d 300 μg Se/d) vs placebo Adherence: NR Serum selenium at 5 yr follow up, μg/L (median (IQR)) G1: 85 (16) G2: 157 (33) G3: 217 (46) G4: 271 (106)	‘Adverse effects’ monitored during the intervention. Method and criteria NR.	25 participants withdrew due to ‘adverse effects’, which included hair loss, skin reactions, grooved nails N of adverse effects, first 6 months/from 7th month until end of study G1: 3/3 G2: 0/5 G3: 2/6 G4: 2/4 35 participants withdrew due to ‘non‐fatal adverse events’ (not described)
Thompson et al. (2016) Sel/Cel USA	RCT G1, placebo: 914/912 G2, 200 μg Se/d: 910/908 Duration (median (max)): 2.75 (0–7.0) yr Aged 40–80 yr; had undergone removal of ≥ 1 colorectal adenomas ≥ 3 mm within 6 mo prior to random assignment; 200 participants had one or more advanced adenomas (i.e., adenomas ≥ 10 mm, villous histology, or high‐grade dysplasia).	Sex (% F) G1: 34.0 G2: 36.7 Age (yr) G1: 62.6 ± 8.9 G2: 63.2 ± 9.0 BMI (kg/m ² ) G1: 29.2 ± 5.1 G2: 29.1 ± 5.1 Ethnicity (white, %) G1: 93.3 G2: 94.4 Plasma Se (μg/L), median (Q1, Q3) G1: 135.2 (120.8, 153.3) G2: 135.5 (121.5, 151.8) Se intake: NR	Selenised yeast (200 μg Se/d) vs placebo Adherence: NR	Adverse events included brittle hair and/or nails. Method and criteria NR.	N of events/participants (event rate/1,000 PY) Brittle hair and/or nails G1: 35/912 (13.8) G2: 30/908 (12.2) HR (95% CI) = 0.86 (0.53, 1.39); p = 0.53
Fairris et al. (1989) USA	RCT G1, placebo: 22/20 G2, 600 μg/d Se: 23/21 G3, 600 μg/d Se + 600 IU vitamin E/d: 24/24 Duration: 12 wk (+12 wk follow up after treatment cessation) Aged 18–70 yr; patients with moderate or severe chronic stable plaque psoriasis	Sex (% F): 51 Age (mean (min‐max), yr) G1: 43 (27–59) G2: 39 (23–66) G3: 44 (20–68) BMI (kg/m ² ): NR Ethnicity: NR Plasma Se (μmol/L) 1.19 ± 0.17 Se intake: NR	Se‐enriched yeast (600 μg Se/d or 600 μg Se/d + 600 IU vitamin E/d) vs placebo Adherence: NR	Adverse events self‐reported at 2, 4, 8, 12 and 24 wk: garlic breath, nausea, vomiting, loss of nails and alopecia. Method and criteria NR.	‘None of the patients developed symptoms or signs that could be related to selenium toxicity’ (Data not shown).

Reference

Study

Country

Design

N randomised/completed

Duration^(a)

Recruitment criteria

Subject characteristics at baseline^(b)

Intervention^(b)

Outcomes assessed

Results

Lippman et al. (2009)

SELECT

USA, Canada, and Puerto Rico

RCT

G1, placebo: 8,856/8,696 G2, 200 μg Se/d: 8,910/8,752 Duration (median (min‐max)): 5.46 (4.17–7.33) yr

Aged ≥ 50 yr (African American men) or ≥ 55 yr (all other men); serum prostate‐specific antigen level ≤ 4 ng/mL; DRE not suspicious for prostate cancer

Sex: M

Age (yr, median (IQR)) G1: 62.6 (58.1–67.8) G2: 62.6 (58.2–68.0)

BMI (kg/m ² ): NR

Ethnicity (Caucasian, %) G1: 79 G2: 79

Serum Se (μg/L, median (IQR)) G1: 137.6 (124.7–151.8) G2: 135.0 (123.4–145.9)

Se intake: NR

L‐selenomethionine (200 μg Se/d) vs placebo

Adherence, pill counts (%) G1: 85% at yr 1; 69% at yr 5

G2: 84% at yr 1; 69% at yr 5

Serum Se at 4 yr follow up, μg/L (median (IQR))

G1: 140.1 (124.3–150.8)

G2: 251.6 (218.7–275.0)

Adverse events self‐reported every 6 months during study site visit (or phone call): alopecia, dermatitis, halitosis, nail changes, fatigue, nausea. NCI Common Toxicity Criteria used for alopecia, nail changes, fatigue, and nausea.

Halitosis and dermatitis defined in study protocol.

RR for adverse events (99% CI)

Alopecia: 1.28 (1.01, 1.62)

Dermatitis grade 1–2: 1.17 (1.00, 1.35)

Dermatitis grade 3–4: 1.74 (0.56, 5.44)

Halitosis: 1.17 (0.99, 1.38)

Nail changes: 1.04 (0.94, 1.16)

Fatigue grade 1–2: 1.09 (0.95, 1.26)

Fatigue grade 3–4: 0.87 (0.40, 1.88)

Nausea grade 1–2: 1.19 (0.94, 1.52)

Nausea grade 3: 0.99 (0.30, 3.34)

Grade 1 = mild, 2 = moderate, 3 = severe, 4 = life‐threatening.

Algotar et al. (2013b)

NBT

USA and New Zealand

RCT

G1, placebo: 232/0 G2, 200 μg Se/d: 234/0 G2, 400 μg Se/d: 233/0

Duration (median): 35 mo

High risk of prostate cancer, as evidenced by PSA > 4 ng/mL and/or suspicious digital rectal examination and/or PSA velocity (rate of PSA change over time) > 0.75 ng/mL per year; undergone a prostate biopsy negative for cancer within 12 mo of enrolment.

Sex: M

Age (yr) G1: 65.5 ± 7.4 G2: 65.2 ± 8.0 G3: 65.5 ± 7.7 BMI (kg/m ² ): NR Ethnicity (Caucasian, %) G1: 84.2 G2: 83.7 G3: 82.6

Plasma Se (μg/L) G1: 124.5 ± 24.7 G2: 126.6 ± 26.9 G3: 127.2 ± 24.8

Se intake: NR

Selenised yeast (200 μg Se/d or 400 μg Se/d or) vs placebo

Adherence, pill counts (%) G1: 92.1 G2: 93.2

G3: 91.2

Adverse events self‐reported to study staff every 6 months during study visit: Brittle nail and hair, garlic breath, liver/kidney abnormality (criteria NR)

N (%) adverse events

Brittle nail and hair:

G1: 26 (11.2) G2: 24 (10.3)

G3: 20 (8.6)

p = 0.63

Garlic breath, liver/kidney abnormality:

G1: 14 (6.0) G2: 13 (5.6)

G3: 11 (4.7)

p = 0.82

Winther et al. (2015)

DK PRECISE

Denmark

RCT

G1, placebo: 126/90

G2, 100 μg Se/d: 124/91

G3, 200 μg Se/d: 122/90

G4, 300 μg Se/d: 119/90

Duration (max): 5 yr

Aged 60–74 yr; taking > 80% pills in the run‐in phase; SWOG performance status score ≤ 1; no active liver or kidney disease; no previous diagnosis of cancer (excluding NMSC); no diagnosed HIV infection; not receiving immunosuppressive therapy; not receiving ≥ 50 mg/day of Se supplements in the previous 6 mo

Sex (% F): 48.1%

Age (yr): 66.1 ± 4.1

BMI (kg/m ² ): NR

Ethnicity: Caucasian

Plasma Se (ng/g, median (IQR))

G1: 85 (20)

G2: 86 (18)

G3: 88 (22)

G4: 84 (19)

Se intake: NR

Se‐enriched yeast (100 μg Se/d or 200 μg Se/d 300 μg Se/d) vs placebo

Adherence: NR

Serum selenium at 5 yr follow up, μg/L (median (IQR))

G1: 85 (16)

G2: 157 (33)

G3: 217 (46)

G4: 271 (106)

‘Adverse effects’ monitored during the intervention. Method and criteria NR.

25 participants withdrew due to ‘adverse effects’, which included hair loss, skin reactions, grooved nails

N of adverse effects, first 6 months/from 7th month until end of study

G1: 3/3

G2: 0/5

G3: 2/6

G4: 2/4

35 participants withdrew due to ‘non‐fatal adverse events’ (not described)

Thompson et al. (2016)

Sel/Cel

USA

RCT

G1, placebo: 914/912 G2, 200 μg Se/d: 910/908

Duration (median (max)): 2.75 (0–7.0) yr

Aged 40–80 yr; had undergone removal of ≥ 1 colorectal adenomas ≥ 3 mm within 6 mo prior to random assignment; 200 participants had one or more advanced adenomas (i.e., adenomas ≥ 10 mm, villous histology, or high‐grade dysplasia).

Sex (% F)

G1: 34.0 G2: 36.7

Age (yr) G1: 62.6 ± 8.9 G2: 63.2 ± 9.0 BMI (kg/m ² )

G1: 29.2 ± 5.1 G2: 29.1 ± 5.1 Ethnicity (white, %) G1: 93.3 G2: 94.4

Plasma Se (μg/L), median (Q1, Q3) G1: 135.2 (120.8, 153.3) G2: 135.5 (121.5, 151.8)

Se intake: NR

Selenised yeast (200 μg Se/d) vs placebo

Adherence: NR

Adverse events included brittle hair and/or nails. Method and criteria NR.

N of events/participants (event rate/1,000 PY)

Brittle hair and/or nails

G1: 35/912 (13.8)

G2: 30/908 (12.2)

HR (95% CI) = 0.86 (0.53, 1.39); p = 0.53

Fairris et al. (1989)

USA

RCT

G1, placebo: 22/20 G2, 600 μg/d Se: 23/21

G3, 600 μg/d Se + 600 IU vitamin E/d: 24/24

Duration: 12 wk (+12 wk follow up after treatment cessation)

Aged 18–70 yr; patients with moderate or severe chronic stable plaque psoriasis

Sex (% F): 51

Age (mean (min‐max), yr)

G1: 43 (27–59) G2: 39 (23–66)

G3: 44 (20–68)

BMI (kg/m ² ): NR

Ethnicity: NR

Plasma Se (μmol/L) 1.19 ± 0.17

Se intake: NR

Se‐enriched yeast (600 μg Se/d or 600 μg Se/d + 600 IU vitamin E/d) vs placebo

Adherence: NR

Adverse events self‐reported at 2, 4, 8, 12 and 24 wk: garlic breath, nausea, vomiting, loss of nails and alopecia. Method and criteria NR.

‘None of the patients developed symptoms or signs that could be related to selenium toxicity’ (Data not shown).

BMI: body mass index; CI: confidence interval; d: day; DK: Denmark; DRE: digital rectal examination; F: females; Gx: group x; HR: hazard ratio; IU: International Unit; IQR: interquartile range; M: males; mo: month; NBT: Negative Biopsy Trial; NCI: National Cancer Institute; NMSC: non‐melanoma skin cancer; NR: Not Reported; PSA: prostate specific antigen; PRECISE: PREvention of Cancer by Intervention with Selenium; PY: person years; Qx: quartile x; RCT: randomised controlled trial; RR: risk ratio; Se: selenium; Sel/Cel: The Selenium and Celecoxib Trial; SELECT: Selenium and Vitamin E Cancer Prevention Trial; SWOG: Southwest Oncology Group; USA: United States of America; wk: week; yr: year.

(a) Duration = duration of the treatment phase, unless specified otherwise.

(b) Mean ± SD, unless specified otherwise.