Scientific opinion on the tolerable upper intake level for selenium

View full-text article in PMC

. 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
Stranges et al. (2007) NPC USA Trial period: 1983–1996	RCT G1, placebo: 659/602 G2, 200 μg Se/d: 653/600 Duration: 7.7 ± 2.7 yr Confirmed history of NMSC in the year before randomisation, estimated life expectancy of 5 yr, and no reported internal cancer in the previous 5 yr, no history of clinically important liver or kidney disorders, no baseline T2DM	Sex (% F) G1: 25 G2: 26 Age (yr) G1: 63.0 ± 9.9 G2: 63.4 ± 10.2 BMI (kg/m ² ) G1: 25.5 ± 4.1 G2: 25.6 ± 3.9 Ethnicity (non‐Hispanic white, %): 98.4 Plasma Se (μg/L) G1: 114.0 ± 21.5 G2: 114.4 ± 22.6 Se intake: NR	Selenised yeast (200 μg/d) vs placebo Adherence, self‐reported (%) G1: 80.3 G2: 78.4	Incidence of T2DM: self‐report during the clinical interview, reported use of drugs for diabetes, and reports in medical record documents. About 92% of reports, regardless of source, were corroborated with medical record documentation (obtained from primary physician and reviewed by blinded nurses).	N T2DM incident cases (N cases/1,000 PY); HRs (95% CI) (adjusted for age, sex, BMI, and smoking status) G1: 39 (8.4)lG2: 58 (12.6); 1.55 (1.03, 2.33) By age ≤ 65 yr: 1.53 (0.83, 2.82) > 65 yr: 1.60 (0.92, 2.76) By sex M: 1.62 (1.04, 2.55) F: 1.38 (0.52, 3.64) By baseline plasma Se median level ≤ 113.4 μg/L : 1.04 (0.60, 1.80) > 113.4 μg/L : 2.50 (1.32, 4.77) By tertile of baseline plasma Se ≤ 105.2 μg/L : 1.13 (0.58, 2.18) 105.3–121.6 μg/L : 1.36 (0.60, 3.09) > 121.6 μg/L : 2.70 (1.30, 5.61)
Lippman et al. (2009) SELECT USA, Canada, and Puerto Rico Trial period: 2001–2008	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/d) vs placebo Adherence, pill counts (%) G1: 85% at yr 1; 69% at yr 5 G2: 84% at yr 1; 69% at yr 5	Incidence of T2DM: self‐reported glitazone medication use (as of beginning of 2003) and self‐report of diabetes (as of beginning of 2005) at each clinic visit; prevalent cases at randomisation excluded	N T2DM incident cases; RR (99% CI) (crude) G1: 699 l G2: 724; 1.07 (0.94, 1.22)
Algotar et al. (2013a) NBT USA and New Zealand Trial period: –	RCT G1, placebo: 232/0 G2, 200 μg Se/d: 234/0 G3, 400 μg Se/d: 233/0 Duration (median (max)): 3 (5) yr High risk of prostate cancer, as evidenced by PSA > 4 ng/mL and/or suspicious DRE 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 (years) 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 or 400 μg Se/day) vs placebo Adherence: NR	Incidence of T2DM: questionnaire at baseline and at every follow‐up visit recorded ‘diabetes status’ (no further information)	N T2DM incident cases G1: 7¦G2: 12lG3: 12; p = 0.44
Karp et al. (2013) ECOG USA Trial period: 2000–2009	RCT G1, placebo: 521/521 G2, 200 μg Se/d: 1,040/1,040 Duration (mean (max)): NR (4) yr Aged ≥ 18 yr; 6 to 36 mo from complete resection of histologically proven non‐small lung cancer; no concurrent cancers or cancer history within the past 5 yr, except localised NMSC; normal hepatic function. Supplements containing ≤ 70 μg Se allowed throughout study participation.	Sex (% F) G1: 52 G2: 51 Age (yr, median (range)) G1: 66 (38–86) G2: 66 (24–93) BMI (kg/m ² ): NR Ethnicity: NR Plasma/serum Se: NR Se intake: NR	Selenised yeast (200 μg Se/day) vs placebo Adherence, reporting taking ‘1 pill a day almost always’: 96% at 3 months, 1 year and 2 years	Incidence of T2DM: diabetes‐related questions added in the on‐study, toxicity, and long‐term follow‐up forms following a recommendation of the DMC in 2007	N T2DM incident cases G1: 12lG2: 26
Thompson et al. (2016) Sel/Cel Trial USA Trial period: 2001–2013	RCT G1, placebo: 914/912 G2, 200 μg Se/d: 910/908 Duration (median, max): 2.75, 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 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/d) vs placebo Adherence, pill count (%) G1: 96.4 G2: 96.6	Incidence of T2DM: development of T2DM (no further description of outcome ascertainment method)	N T2DM incident cases (N cases/1,000 PY); HRs (95% CI) (adjusted for random assignment to celecoxib, aspirin, and clinic) G1: 25 (11.0) l G2: 31 (13.7); 1.25 (0.74, 2.11) By sex F: G1: 6 (8) l G2: 12 (15); 1.85 (0.69, 4.97) M: G1: 19 (12.5) l G2: 19 (13); 1.05 (0.56, 1.99) By age < 63 y: G1: 15 (13.5) l G2: 9 (8.1); 0.59 (0.25, 1.35) ≥ 63 y: G1: 10 (8.6) l G2: 22 (19.2); 2.21 (1.04, 4.67)

Reference

Study

Country

Design

N randomised/completed

Duration^(a)

Recruitment criteria

Subject characteristics at baseline^(b)

Intervention^(b)

Outcomes assessed

Results

Stranges et al. (2007)

NPC

USA

Trial period: 1983–1996

RCT

G1, placebo: 659/602 G2, 200 μg Se/d: 653/600

Duration: 7.7 ± 2.7 yr

Confirmed history of NMSC in the year before randomisation, estimated life expectancy of 5 yr, and no reported internal cancer in the previous 5 yr, no history of clinically important liver or kidney disorders, no baseline T2DM

Sex (% F)

G1: 25 G2: 26

Age (yr) G1: 63.0 ± 9.9 G2: 63.4 ± 10.2

BMI (kg/m ² )

G1: 25.5 ± 4.1 G2: 25.6 ± 3.9

Ethnicity (non‐Hispanic white, %): 98.4

Plasma Se (μg/L) G1: 114.0 ± 21.5 G2: 114.4 ± 22.6

Se intake: NR

Selenised yeast (200 μg/d) vs placebo

Adherence, self‐reported (%) G1: 80.3 G2: 78.4

Incidence of T2DM: self‐report during the clinical interview, reported use of drugs for diabetes, and reports in medical record documents. About 92% of reports, regardless of source, were corroborated with medical record documentation (obtained from primary physician and reviewed by blinded nurses).

N T2DM incident cases (N cases/1,000 PY); HRs (95% CI) (adjusted for age, sex, BMI, and smoking status)

G1: 39 (8.4)lG2: 58 (12.6); 1.55 (1.03, 2.33)

By age

≤ 65 yr: 1.53 (0.83, 2.82)

> 65 yr: 1.60 (0.92, 2.76)

By sex

M: 1.62 (1.04, 2.55) F: 1.38 (0.52, 3.64)

By baseline plasma Se median level ≤ 113.4 μg/L : 1.04 (0.60, 1.80) > 113.4 μg/L : 2.50 (1.32, 4.77)

By tertile of baseline plasma Se

≤ 105.2 μg/L : 1.13 (0.58, 2.18) 105.3–121.6 μg/L : 1.36 (0.60, 3.09)

> 121.6 μg/L : 2.70 (1.30, 5.61)

Lippman et al. (2009)

SELECT

USA, Canada, and Puerto Rico

Trial period: 2001–2008

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/d) vs placebo

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

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

Incidence of T2DM: self‐reported glitazone medication use (as of beginning of 2003) and self‐report of diabetes (as of beginning of 2005) at each clinic visit; prevalent cases at randomisation excluded

N T2DM incident cases; RR (99% CI) (crude)

G1: 699 l G2: 724; 1.07 (0.94, 1.22)

Algotar et al. (2013a)

NBT

USA and New Zealand

Trial period: –

RCT

G1, placebo: 232/0 G2, 200 μg Se/d: 234/0 G3, 400 μg Se/d: 233/0

Duration (median (max)): 3 (5) yr

High risk of prostate cancer, as evidenced by PSA > 4 ng/mL and/or suspicious DRE 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 (years) 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 or 400 μg Se/day) vs placebo

Adherence: NR

Incidence of T2DM: questionnaire at baseline and at every follow‐up visit recorded ‘diabetes status’ (no further information)

N T2DM incident cases

G1: 7¦G2: 12lG3: 12; p = 0.44

Karp et al. (2013)

ECOG

USA

Trial period: 2000–2009

RCT

G1, placebo: 521/521 G2, 200 μg Se/d: 1,040/1,040

Duration (mean (max)): NR (4) yr

Aged ≥ 18 yr; 6 to 36 mo from complete resection of histologically proven non‐small lung cancer; no concurrent cancers or cancer history within the past 5 yr, except localised NMSC; normal hepatic function. Supplements containing ≤ 70 μg Se allowed throughout study participation.

Sex (% F)

G1: 52

G2: 51

Age (yr, median (range))

G1: 66 (38–86)

G2: 66 (24–93) BMI (kg/m ² ): NR

Ethnicity: NR

Plasma/serum Se: NR

Se intake: NR

Selenised yeast (200 μg Se/day) vs placebo

Adherence, reporting taking ‘1 pill a day almost always’: 96% at 3 months, 1 year and 2 years

Incidence of T2DM: diabetes‐related questions added in the on‐study, toxicity, and long‐term follow‐up forms following a recommendation of the DMC in 2007

N T2DM incident cases

G1: 12lG2: 26

Thompson et al. (2016)

Sel/Cel Trial

USA

Trial period: 2001–2013

RCT

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

Duration (median, max): 2.75, 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 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/d) vs placebo

Adherence, pill count (%) G1: 96.4 G2: 96.6

Incidence of T2DM:

development of T2DM (no further description of outcome ascertainment method)

N T2DM incident cases (N cases/1,000 PY); HRs (95% CI) (adjusted for random assignment to celecoxib, aspirin, and clinic)

G1: 25 (11.0) l G2: 31 (13.7); 1.25 (0.74, 2.11)

By sex

F: G1: 6 (8) l G2: 12 (15); 1.85 (0.69, 4.97)

M: G1: 19 (12.5) l G2: 19 (13); 1.05 (0.56, 1.99)

By age

< 63 y: G1: 15 (13.5) l G2: 9 (8.1); 0.59 (0.25, 1.35)

≥ 63 y: G1: 10 (8.6) l G2: 22 (19.2); 2.21 (1.04, 4.67)

BMI: body mass index; CI: confidence interval; d: day; DRE: digital rectal examination; ECOG: Eastern Cooperative Oncology Group; F: females; Gx: group x; HR: hazard ratio; IQR: interquartile range; M: males; mo: month; N: number; NBT: Negative Biopsy Trial; NMSC: non‐melanoma skin cancer; NPC: Nutritional Prevention of Cancer trial; PSA: prostate specific antigen; PY: person‐years; RCT: randomised controlled trial; RR: relative risk; Se: selenium; Sel/Cel: Selenium and Celecoxib trial; SD: standard deviation; SELECT: Selenium and Vitamin E Cancer Prevention Trial; Qx: quartile x; T2DM: type 2 diabetes mellitus; 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.