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
Duffield‐Lillico et al. (2003b) Duffield‐Lillico et al. (2002) NPC USA	RCT G1, placebo: 629/465 G2, 200 μg Se/d: 621/472 Duration (mean, max): 7.6 yr; 13 yr Confirmed histories of NMSC within the year before randomisation; estimated 5‐yr life‐expectancy; no cancer within the previous 5 yr.	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 Se/d) vs placebo Adherence, % missing a pill less than twice a month (self‐reported): G1: 80 G2: 78	Incident BCC and SCC diagnosed by biopsy and confirmed by board‐certified dermatopathologists. Recurrent and retreated skin tumours and skin tumours without biopsy confirmation were excluded	Incidence rate (N cases/total PY); HR (95% CI) (adjusted for sex, age, smoking status, clinic site, plasma Se, clinical sun damage, sunscreen use at baseline, and N of BCCs/SCCs/total NMSCs (analysis dependent) in previous 12 mo) SCC G1: 0.05¦G2: 0.07; 1.25 (1.03, 1.51) By tertile of baseline plasma Se concentration (μg/L) ≤ 105.2 μg/L: 0.87 (0.62, 1.22) 105.6–122 μg/L: 1.49 (1.05, 2.12) ≥ 122.4 μg/L: 1.59 (1.11, 2.30) BCC G1: 0.13¦G2: 0.16; 1.09 (0.94, 1.26) Total NMSC G1: 0.16¦G2: 0.20; 1.17 (1.02, 1.34) N incident cases; HR (95% CI) (adjusted for age, smoking status and gender) Melanoma G1: 9¦G2: 11; 1.18 (0.49, 2.85)
Reid et al. (2008) NPC (Macon site) USA	RCT G1, placebo: 213 G2, 400 μg Se/d: 210 Duration (mean): 5.2 yr Confirmed history of NMSC in the year before randomisation, had an estimated life expectancy of 5 yr, and had no reported internal cancer in the previous 5 yr	Sex (% F) G1: 31.9 G2: 33.8 Age (yr) G1: 63.8 ± 10.1 G2: 63.8 ± 10.6 Ethnicity (non‐Hispanic white, %): 98.4 BMI (kg/m ² ) G1: 26.1 ± 3.9 G2: 25.7 ± 3.8 Plasma Se (μg/L) G1: 114.0 ± 18.1 G2: 119.0 ± 24.3 Se intake NR	Selenised yeast (400 μg Se/d) vs placebo Adherence, % missing a pill less than twice a month (self‐reported): G1: 81 G2: 78	Incident BCC and SCC diagnosed by biopsy and confirmed by board‐certified dermatopathologists. Recurrent and retreated skin tumours and skin tumours without biopsy confirmation excluded	N incident cases; HR (95% CI) (adjusted for age, smoking status and gender) SCC G1: 53¦G2: 56; 1.05 (0.72, 1.53) BCC G1: 83¦G2: 76; 0.95 (0.69, 1.29) Total NMSC G1: 108¦G2: 98; 0.91 (0.69, 1.20) By tertile of baseline plasma Se ≤ 106.8 μg/L : 0.95 (0.57, 1.55) 106.8–122.4 μg/L : 0.94 (0.57, 1.53) > 122.4 μg/L : 0.79 (0.46, 1.34) By median baseline plasma Se < 113.2 μg/L : 0.98 (0.65, 1.46) ≥ 113.2 μg/L : 0.80 (0.53, 1.21)
Thompson et al. (2016) Sel/Cel USA	RCT G1, placebo: 914/912 G2, 200 μg Se/d: 910/908 Duration (median): 33 mo Aged 40–80 yrs; 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 Personal history of skin cancer, n (%) G1: 144 (15.8) G2: 142 (15.6) Personal history of SCC, n (%) G1: 28 (3.1) G2: 33 (3.6)	Selenised yeast (200 μg Se/d) vs placebo Adherence: NR	Incident SCC; method of ascertainment NR	N incident cases SCC (event rate/1,000 PY); HR (95% CI) (adjusted for random assignment to celecoxib, aspirin, and clinic) G1: 21 (8.2)¦G2: 27 (10.9); 1.34 (0.76, 2.37) Stratified by sex F: G1: 5 (6.2)¦G2: 3 (3.4); 0.52 (0.13, 2.20) M: G1: 16 (9.2)¦G2: 24 (15.2); 1.64 (0.87, 3.09) Among participants with history of SCC at baseline G1: 5 (68.8)¦G2: 6 (78.3); 1.09 (0.30, 4.04)
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 prostate specific antigen (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 (Caucasians, %) G1: 84.2 G2: 83.7 G3: 82.6 Plasma Se (μg/L) G1: 124.5 ± 24.7G2: 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	Incidence of melanoma, BCC and SCC; method of ascertainment NR	N incident cases Melanoma G1: 2¦G2: 3¦G3: 2 (p = 0.87) BCC G1: 15¦G2: 13¦G3: 12 (p = 0.82) SCC G1: 17¦G2: 10¦G3: 2 (p = 0.002)

Reference

Study

Country

Design

N randomised/completed

Duration^(a)

Recruitment criteria

Subject characteristics at baseline^(b)

Intervention^(b)

Outcomes assessed

Results

Duffield‐Lillico et al. (2003b)

Duffield‐Lillico et al. (2002)

NPC

USA

RCT

G1, placebo: 629/465

G2, 200 μg Se/d: 621/472

Duration (mean, max): 7.6 yr; 13 yr

Confirmed histories of NMSC within the year before randomisation; estimated 5‐yr life‐expectancy; no cancer within the previous 5 yr.

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 Se/d) vs placebo

Adherence, % missing a pill less than twice

a month (self‐reported):

G1: 80

G2: 78

Incident BCC and SCC diagnosed by biopsy and confirmed by board‐certified dermatopathologists.

Recurrent and retreated skin tumours and skin tumours without biopsy confirmation were excluded

Incidence rate (N cases/total PY); HR (95% CI) (adjusted for sex, age, smoking status, clinic site, plasma Se, clinical sun damage, sunscreen use at baseline, and N of BCCs/SCCs/total NMSCs (analysis dependent) in previous 12 mo)

SCC

G1: 0.05¦G2: 0.07; 1.25 (1.03, 1.51)

By tertile of baseline plasma Se concentration (μg/L)

≤ 105.2 μg/L: 0.87 (0.62, 1.22)

105.6–122 μg/L: 1.49 (1.05, 2.12)

≥ 122.4 μg/L: 1.59 (1.11, 2.30)

BCC

G1: 0.13¦G2: 0.16; 1.09 (0.94, 1.26)

Total NMSC

G1: 0.16¦G2: 0.20; 1.17 (1.02, 1.34)

N incident cases; HR (95% CI) (adjusted for age, smoking status and gender)

Melanoma

G1: 9¦G2: 11; 1.18 (0.49, 2.85)

Reid et al. (2008)

NPC (Macon site)

USA

RCT

G1, placebo: 213

G2, 400 μg Se/d: 210

Duration (mean): 5.2 yr

Confirmed history of NMSC in the year before randomisation, had an estimated life expectancy of 5 yr, and had no reported internal cancer in the previous 5 yr

Sex (% F)

G1: 31.9

G2: 33.8

Age (yr)

G1: 63.8 ± 10.1

G2: 63.8 ± 10.6

Ethnicity (non‐Hispanic white, %): 98.4

BMI (kg/m ² )

G1: 26.1 ± 3.9

G2: 25.7 ± 3.8

Plasma Se (μg/L)

G1: 114.0 ± 18.1

G2: 119.0 ± 24.3

Se intake NR

Selenised yeast (400 μg Se/d) vs placebo

Adherence, % missing a pill less than twice

a month (self‐reported):

G1: 81

G2: 78

Incident BCC and SCC diagnosed by biopsy and confirmed by board‐certified dermatopathologists.

Recurrent and retreated skin tumours and skin tumours without biopsy confirmation excluded

N incident cases; HR (95% CI) (adjusted for age, smoking status and gender)

SCC

G1: 53¦G2: 56; 1.05 (0.72, 1.53)

BCC

G1: 83¦G2: 76; 0.95 (0.69, 1.29)

Total NMSC

G1: 108¦G2: 98; 0.91 (0.69, 1.20)

By tertile of baseline plasma Se

≤ 106.8 μg/L : 0.95 (0.57, 1.55)

106.8–122.4 μg/L : 0.94 (0.57, 1.53)

> 122.4 μg/L : 0.79 (0.46, 1.34)

By median baseline plasma Se

< 113.2 μg/L : 0.98 (0.65, 1.46)

≥ 113.2 μg/L : 0.80 (0.53, 1.21)

Thompson et al. (2016)

Sel/Cel

USA

RCT

G1, placebo: 914/912

G2, 200 μg Se/d: 910/908

Duration (median): 33 mo

Aged 40–80 yrs; 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

Personal history of skin cancer, n (%)

G1: 144 (15.8)

G2: 142 (15.6)

Personal history of SCC, n (%)

G1: 28 (3.1)

G2: 33 (3.6)

Selenised yeast (200 μg Se/d) vs placebo

Adherence: NR

Incident SCC; method of ascertainment NR

N incident cases SCC (event rate/1,000 PY); HR (95% CI) (adjusted for random assignment to celecoxib, aspirin, and clinic)

G1: 21 (8.2)¦G2: 27 (10.9); 1.34 (0.76, 2.37)

Stratified by sex

F: G1: 5 (6.2)¦G2: 3 (3.4); 0.52 (0.13, 2.20)

M: G1: 16 (9.2)¦G2: 24 (15.2); 1.64 (0.87, 3.09)

Among participants with history of SCC at baseline

G1: 5 (68.8)¦G2: 6 (78.3); 1.09 (0.30, 4.04)

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 prostate specific antigen (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 (Caucasians, %) G1: 84.2 G2: 83.7 G3: 82.6

Plasma Se (μg/L) G1: 124.5 ± 24.7G2: 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

Incidence of melanoma, BCC and SCC; method of ascertainment NR

N incident cases

Melanoma

G1: 2¦G2: 3¦G3: 2 (p = 0.87)

BCC

G1: 15¦G2: 13¦G3: 12 (p = 0.82)

SCC

G1: 17¦G2: 10¦G3: 2 (p = 0.002)

BCC: basal cell carcinoma; BMI: body mass index; CI: confidence interval; d: day; F: females; Gx: group x; HR: hazard ratio; M: males; mo: month; N: number; NBT: Negative Biopsy Trial; NMSC: non‐melanoma skin cancer; NPC: Nutritional Prevention of Cancer Trial; NR: not reported; NZ: New Zealand; PY: person‐years; Qx: quartile x; SCC: squamous cell carcinoma; SD: standard deviation; Se: selenium; Sel/Cel: The Selenium and Celecoxib Trial; USA: United States of America; yr: year.

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

(b): Mean ± SD, unless specified otherwise.