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^(b)
Rayman et al. (2008b) UK PRECISE pilot study UK	RCT G1, placebo: 121/90 G2, 100 Se μg/d: 127/99 G3, 200 Se μg/d: 127/95 G4, 300 Se μg/d: 126/84 Duration: 6 mo Euthyroid volunteers; TSH at baseline within the reference range (0.15–3.5 mU/L); SWOG performance status score ≤ 1; no active liver or kidney disease; no prior diagnosis of cancer (excluding nonmelanoma skin cancer); no diagnosis of HIV infection; not on immunosuppressive therapy; not diminished mental capacity; not taking ≥ 50 μg/d of Se supplements in the previous 6 mo.	Sex (% F): 44 Age, range: 60–74 yr BMI (kg/m ² ): NR Ethnicity: Caucasian Plasma Se (ng/g, mean (95% CI)): 88.9 (86.9, 90.8) Se intake: NR	Se‐enriched yeast (100 μg Se/d or 200 μg Se/d or 300 μg Se/d) vs placebo Adherence, pill counts (%): 97% participants missed < 10% pills Increase in plasma Se at 6 mo follow up, ng/g (mean (95% CI)) G1: 0 G2: +53.5 (48.2, 58.8) G3: +96.4 (89.2, 103.6) G4: +129.7 (119.9, 139.5)	Plasma levels of T3, FT3, T4, FT4, T3:T4, FT3:FT4, TSH	T3 (nmol/L) G1: 1.80 ± 0.30 G2: 1.81 ± 0.23 G3: 1.82 ± 0.49 G4: 1.73 ± 0.27 FT3 (pmol/L) G1: 5.25 ± 0.57 G2: 5.14 ± 0.62 G3: 5.14 ± 0.62 G4: 5.17 ± 0.56 T4 (nmol/L) G1: 86.5 ± 17.3 G2: 87.7 ± 18.1 G3: 85.6 ± 15.9 G4: 82.7 ± 15.8 FT4 (pmol/L) G1: 12.2 ± 2.1 G2: 11.8 ± 1.6 G3: 12.0 ± 1.8 G4: 11.6 ± 1.9 T3:T4 (x10 ⁻² ) G1: 2.13 ± 0.43 G2: 2.12 ± 0.40 G3: 2.16 ± 0.50 G4: 2.14 ± 0.44 FT3:FT4 G1: 0.44 ± 0.08 G2: 0.44 ± 0.06 G3: 0.44 ± 0.08 G4: 0.45 ± 0.07 TSH (mU/L) G1: 1.17 ± 0.66 G2: 1.24 ± 0.73 G3: 1.20 ± 0.61 G4: 1.21 ± 0.61	T3 (nmol/L) G1: 1.79 ± 0.23 G2: 1.78 ± 0.22 G3: 1.80 ± 0.47 G4: 1.72 ± 0.25 Adj p = 0.56* FT3 (pmol/L) G1: 5.25 ± 0.61 G2: 5.15 ± 0.65 G3: 5.22 ± 0.55 G4: 5.17 ± 0.59 Adj p = 0.45* T4 (nmol/L) G1: 87.2 ± 18.0 G2: 87.0 ± 16.4 G3: 83.5 ± 14.5 G4: 81.6 ± 14.4 Adj p = 0.10* FT4 (pmol/L) G1: 12.1 ± 2.1 G2: 11.9 ± 1.6 G3: 11.9 ± 1.8 G4: 11.6 ± 1.7 Adj p = 0.92* T3:T4 (× 10 ⁻² ) G1: 2.12 ± 0.41 G2: 2.09 ± 0.37 G3: 2.19 ± 0.46 G4: 2.15 ± 0.43 Adj p = 0.37* FT3:FT4 G1: 0.44 ± 0.09 G2: 0.44 ± 0.07 G3: 0.45 ± 0.08 G4: 0.45 ± 0.07 Adj p = 0.41* TSH (mU/L) G1: 1.23 ± 0.72 G2: 1.23 ± 0.70 G3: 1.27 ± 0.69 G4: 1.18 ± 0.69 Adj p = 0.24* *Between‐groups comparisons (ANCOVA; adjusted for baseline value, sex, age, and clinic location)
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)	Plasma levels of FT3, FT4, FT3:FT4, TSH	FT3 (pmol/L, median (IQR)) G1: 5.44 (0.77) G2: 5.56 (0.71) G3: 5.54 (0.68) G4: 5.56 (0.83) FT4 (pmol/L, median (IQR)) G1: 12.88 (2.67) G2: 13.06 (2.8) G3: 13.43 (2.28) G4: 13.43 (2.38) FT3:FT4 (median, IQR)) G1: 0.43 (0.07) G2: 0.43 (0.10) G3: 0.42 (0.07) G4: 0.42 (0.07) TSH (mU/L, median (IQR)) G1: 1.21 (0.81) G2: 1.28 (0.94) G3: 1.14 (0.95) G4: 1.18 (0.89)	FT3 (pmol/L, median (IQR)) G1: 5.54 (0.95) G2: 5.59 (0.71) G3: 5.58 (0.78) G4: 5.53 (0.78) FT4 (pmol/L, median (IQR)) G1: 13.32 (3.07) G2: 13.52 (2.88) G3: 13.24 (2.08) G4: 13.25 (2.12) FT3:FT4 (median, IQR)) G1: 0.42 (0.09) G2: 0.42 (0.09) G3: 0.42 (0.07) G4: 0.42 (0.08) TSH (mU/L, median (IQR)) G1: 1.22 (1.02) G2: 1.17 (0.79) G3: 1.32 (0.84) G4: 1.06 (0.85)
Carvalho et al. (2015) Brazil	RCT G1, placebo: 45/42 G2, 227.5 μg Se/day: 44/35 Duration: 90 d Aged 40–80 yr; with dyslipidemia and hypertension and treated for both conditions in the previous 3 mo; TSH within reference range (0.45–4.50 μUI/mL) and FT4 within reference range (0.70–1.48 ng/dL); no history of thyroid disease or thyroid medication use; no chronic renal failure; not using supplements containing > 20 μg Se/day; no excessive consumption of Brazil nuts; not having plasma Se levels > 125 μg/L; not being current smokers; not having been in a rigorous exercise/ weight‐reduction program in the previous 3 mo	Sex (% F): 44.2 Age (yr): 60.05 ± 10.27 BMI (kg/m ² ): 29.54 ± 5.60 Ethnicity: NR Plasma Se (μg/L) G1: 86.6 ± 17.2 G2: 88.7 ± 15.3 Se intake: NR	13 g/day partially defatted Brazil nut flour (227.5 μg of Se/d) vs 11 g/day of artificially flavoured dyed cassava flour as placebo (0.07 μg Se/d) Plasma Se at 90 d follow up, μg/L G1: 92.7 ± 16.8 G2: 169.5 ± 46.5	Plasma levels of FT3, FT4, TSH	NR	Change from baseline FT3 (pg/mL) G1: −0.1 ± 0.4 G2: 0.1 ± 1.1 p = 0.030, for intragroup differences in G1, compared to baseline values NS, for intragroup differences in G2 or intergroup differences at end of trial FT4 (ng/dL) G1: −0.1 ± 0.1 G2: 0.1 ± 0.6 NS, for intragroup differences in G1 and G2, or intergroup differences at end of trial TSH (μUI/mL) G1: −0.2 ± 0.9 G2: 0.2 ± 1.8 NS, for intragroup differences in G1 and G2. p = 0.06 for intergroup differences at end of trial
Thomson et al. (2009) New Zealand	RCT G1, placebo: 25/24 G2, 100 Se μg/d: 25/25 Duration: 12 wk Aged 60–80 yr; noninstitutionalised, free from cancer, diabetes, or cardiovascular disease; not using medications for thyroid function or with any known thyroid problems; not taking supplements containing Se or iodine.	Sex (% F): 55 Age (yr): 72.4 ± 4.8 BMI (kg/m ² ): 26.8 ± 5.8 Ethnicity: NR Plasma Se (μmol/L) G1: 1.23 ± 0.29 G2: 1.23 ± 0.31 Se intake: NR	L‐Selenomethionine (100 Se μg/d) vs placebo Adherence: 90% of consuming all pills and 10% consuming between 97% and 99% pills.	Plasma levels of FT3, FT4, FT3:FT4, TSH	FT3 (pmol/L) G1: 4.85 ± 0.47 G2: 4.70 ± 0.46 FT4 (pmol/L) G1: 14.7 ± 2.0 G2: 14.0 ± 2.0 FT3:FT4 (median, IQR)) G1: 0.33 (0.31, 0.37) G2: 0.34 (0.30, 0.39) TSH (mIU/L, median (IQR)) G1: 2.35 (1.59, 3.41) G2: 2.58 (1.76, 3.23)	Change from baseline FT3 (geometric mean (95% CI)) G1: −0.10 (20.27, 0.08), p = 0.267* G2: 0.15 (20.02, 0.31), p = 0.080* FT4 (geometric mean (95% CI)) G1: −0.16 (20.65, 0.33), p = 0.521* G2: 0.04 (20.43, 0.51), p = 0.881* *Random‐coefficients mixed model, adjusted for age, sex, BMI, baseline plasma Se, medication use, and supplement use
Thomson et al. (2005) Study 3: Dunedin smokers New Zealand	RCT G1, placebo: 30 G2, 100 μg Se/d: 30 Duration: 20 wk Aged 19–52 yr; smokers; whole blood Se concentration < 1.0 mmol/L, or whole blood Se concentration between 1.0–1.2 mmol/L and whole blood glutathione peroxidase activities < 20 units/g Hb	Sex (% F): 50 Age (yr): 19–52 BMI (kg/m ² ): NR Ethnicity: NR Plasma Se (μmol/L) G1: 0.99 ± 0.15 G2: 0.97 ± 0.14 Se intake: NR	L‐Selenomethionine (100 μg Se/day) vs placebo Adherence: NR	Plasma levels of T3, T4, TSH	T4 (μmol/L) G1: 99 ± 31 G2: 106 ± 36 T3:T4 G1: 0.021 ± 0.009 G2: 0.022 ± 0.008 TSH NR	T4 (μmol/L) G1: 91 ± 32 G2: 98 ± 33 p = NS T3:T4 G1: 0.020 ± 0.007 G2: 0.023 ± 0.008 p = NS TSH NR
Thomson et al. (2005) Study 5: Dunedin residents New Zealand	RCT G1, placebo: 86 G2, 200 μg Se/d: 86 Duration: 20 wk Aged 18–65 years, healthy	Sex (% F): 66.28 Age (yr): 18–65 BMI (kg/m ² ): NR Ethnicity: NR Plasma Se (μmol/L) G1: 1.06 ± 0.23 G2: 1.14 ± 0.28 Se intake: NR	Se‐enriched yeast (200 μg Se/d) vs placebo Adherence: NR	Plasma levels of T3, T4, TSH	T4 (μmol/L) G1: 89 ± 18 G2: 88 ± 23 T3:T4 G1: 0.018 ± 0.003 G2: 0.019 ± 0.006 TSH NR	T4 (μmol/L) G1: 88 ± 23 G2: 84 ± 22 p = NS T3:T4 G1: 0.018 ± 0.005 G2: 0.018 ± 0.004 p = NS TSH NR
Hawkes et al. (2008) USA	RCT G1, placebo: 20 G2, 300 μg Se/d: 22 Duration: 48 wk No hypertension, diabetes, sexually transmitted disease, or cancer; clinically normal blood count, blood chemistries and thyrotropin; no smokers; no use of Se shampoos, Se supplements > 50 mg/d, thyroid medications, weight loss drugs, or anabolic steroids; not > 10 lb weight change within last 6 mo; no exercise or physical training in excess of 3 × 1‐h sessions per wk.	Sex: M Age (yr): 18–45 BW (kg): G1: 77.4 ± 11.9 G2: 76.3 ± 9.9 Ethnicity: NR Plasma Se: NR Se intake (3‐d diet record): 135 ± 57 μg/d	Se‐enriched yeast (300 μg Se/d) vs placebo Adherence, pills count (%): 93 ± 5.3	Plasma levels of T3, FT3, T4, FT4, TSH	T3 (nmol/L) G1: 1.90 ± 0.38 G2: 2.17 ± 0.43 FT3 (pmol/L) G1: 41 ± 11 G2: 45 ± 7.5 T4 (nmol/L) G1: 91 ± 17 G2: 94 ± 17 FT4 (nmol/L) G1: 18 ± 2.7 G2: 18 ± 2.7 TSH (mU/L) G1: 2.30 ± 1.31 G2: 2.10 ± 0.85	T3 (nmol/L) G1: 1.77 ± 0.28 G2: 1.98 ± 0.35 p = NS FT3 (pmol/L) G1: 39 ± 7.5 G2: 45 ± 17 p = NS T4 (nmol/L) G1: 92 ± 18 G2: 92 ± 22 p = NS FT4 (nmol/L) G1: 18 ± 3.0 G2: 18 ± 2.2 p = NS TSH (mU/L) G1: 2.16 ± 1.11 G2: 2.11 ± 1.10 p = NS
Hawkes and Keim (2003) USA	RCT G1, low Se diet: 6/6 G2, high Se diet: 6/5 Duration: 99 d Healthy; BW for height 125% of ideal; no use of Se supplements or Se‐containing shampoos; normal ECG, blood cell counts, clinical chemistries or semen analysis; no HIV infection; no use of illegal drugs; no use of tobacco or alcohol; no use of medications; no history of psychiatric illness, thyroid or heart disease, syphilis, hepatitis, diabetes, hypertension or hyperlipidaemia.	Sex: M Age (yr): 20–45 BW (kg): G1: 74.9 ± 9.8 G2: 73.5 ± 12.6 Ethnicity: NR Plasma Se (μg/L)* G1: 118 ± 8 G2: 107 ± 19 Se intake: NR	Stabilisation period: 47 μg/day of Se for 21‐d; then randomised to receive foods with naturally high (297 μg/d) or low (14 μg/d) Se content; diet controlled in metabolic research unit.	Plasma levels of T3, T4, TSH	T3 (nmol/L)* G1: 1.57 ± 0.25 G2: 1.82 ± 0.36 T4 (nmol/L)* G1: 118 ± 26 G2: 113 ± 15 TSH (mU/L)* G1: 1.69 ± 0.30 G2: 2.25 ± 0.81 * Values at 21‐d (end of stabilisation period)	T3 (nmol/L) G1: 1.64 ± 0.16 G2: 1.57 ± 0.07 p Se = 0.013; p time = NS; p Se × time = 0.048^# T4 (nmol/L) G1: 90.3 ± 6.6 G2: 86.8 ± 12.7 p Se = NS; p time = 0.033; p Se × time model = NS^# TSH (mU/L) G1: 1.77 ± 0.46 G2: 2.96 ± 1.05 p Se = NS; p time = 0.011; p Se × time = 0.031^# ^#Repeated‐measures ANOVA, controlling for baseline values
Duffield and Thomson (1999) New Zealand	RCT G1, placebo: 10 G2, 10 Se μg/d: 10 G3, 20 Se μg/d: 11 G4, 30 Se μg/d: 10 G5, 40 Se μg/d: 11 Duration: 20 wk New Zealand residents; whole‐blood Se concentrations < 1.26 mmol/L	Sex (% F): 67.31 Age (yr): 19–59 y BW (kg): G1: 78.5 G2: 66.4 G3: 76.6 G4: 79.4 G5: 67.8 Ethnicity: NR Plasma Se (μmol/L) G1: 0.783 G2: 0.806 G3: 0.846 G4: 0.869 G5: 0.809 Se intake (μg/day) 3‐d duplicate diets: 29 ± 13 3‐d diet records: 28 ± 15	L‐selenomethionine (10 Se μg/day, 20 Se μg/day, 30 Se μg/day or 40 Se μg/day) vs placebo Adherence (assessed by pill counts) NR Increase in whole‐blood Se at 20 kw follow up vs baseline, % (mean) G1: +4 G2: +9 G3: +9 G4: +7 G5: +13	Plasma levels of T4	T4 (nmol/L) G1: 95 ± 32 G2: 108 ± 21 G3: 97 ± 15 G4: 97 ± 18 G5: 95 ± 23	T4 (nmol/L) G1: 99 ± 30 G2: 93 ± 10* G3: 88 ± 15 G4: 90 ± 17 G5: 89 ± 19 G2‐G5 (combined): 89 ± 15* *Significantly different from week 0 after adjustment for baseline value, p < 0.05
Olivieri et al. (1995) Italy	RCT G1, placebo: 20/17 G2, 100 Se μg/d: 20/19 Duration: 3 mo No nutritional disturbances, thyroid or gastrointestinal diseases that could influence thyroid hormones or Se status; not taking supplements.	Sex (% F): 77.8 Age (yr): 85 ± 7 Ethnicity: Caucasian Serum Se (μmol/L) G1: 0.79 ± 0.18 G2: 0.83 ± 0.13 Se intake: NR	Sodium selenite (100 Se μg/d) vs placebo Adherence: tablets given during breakfast over the supervision of a nurse. Serum Se increased by 61% in the supplemented participants vs no change in the control group	Plasma levels of T3, T4, FT4, T3:T4, TSH	T3 (nmol/L) G1: 1.1 ± 0.17 G2: 1.08 ± 0.14 T4 (nmol/L) G1: 70 ± 13 G2: 67 ± 9 FT4 (pmol/L) G1: 9.99 ± 2.2 G2: 9.4 ± 1.5 T3:T4 G1: 0.016 ± 0.003 G2: 0.016 ± 0.002 TSH (mU/L) G1: 1.14 ± 0.51 G2: 1.2 ± 0.5	T3 (nmol/L) G1: 1.1 ± 0.09 G2: 0.99 ± 0.2 T4 (nmol/L) G1: 68.5 ± 10.4 G2: 62 ± 10* FT4 (pmol/L) G1: 10 ± 1.65 G2: 9.3 ± 2 T3:T4 G1: 0.015 ± 0.002 G2: 0.016 ± 0.003 TSH (mU/L) G1: 0.99 ± 0.71 G2: 1.18 ± 0.58 *paired Student t‐test: significant difference between values at baseline vs end of trial (p < 0.05).

Reference

Study

Country

Design

N randomised/completed

Duration^(a)

Recruitment criteria

Subject characteristics at baseline^(b)

Intervention^(b)

Outcomes assessed

Results^(b)

Baseline

End of trial

Rayman et al. (2008b)

UK PRECISE

pilot study

RCT

G1, placebo: 121/90

G2, 100 Se μg/d: 127/99

G3, 200 Se μg/d: 127/95

G4, 300 Se μg/d: 126/84

Duration: 6 mo

Euthyroid volunteers; TSH at baseline within the reference range (0.15–3.5 mU/L); SWOG performance status score ≤ 1; no active liver or kidney disease; no prior diagnosis of cancer (excluding nonmelanoma skin cancer); no diagnosis of HIV infection; not on immunosuppressive therapy; not diminished mental capacity; not taking ≥ 50 μg/d of Se supplements in the previous 6 mo.

Sex (% F): 44

Age, range: 60–74 yr

BMI (kg/m ² ): NR

Ethnicity: Caucasian

Plasma Se (ng/g, mean (95% CI)): 88.9 (86.9, 90.8)

Se intake: NR

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

Adherence, pill counts (%): 97% participants

missed < 10% pills

Increase in plasma Se at 6 mo follow up, ng/g (mean (95% CI))

G1: 0

G2: +53.5 (48.2, 58.8)

G3: +96.4 (89.2, 103.6)

G4: +129.7 (119.9, 139.5)

Plasma levels of T3, FT3, T4, FT4, T3:T4, FT3:FT4, TSH

T3 (nmol/L)

G1: 1.80 ± 0.30

G2: 1.81 ± 0.23

G3: 1.82 ± 0.49

G4: 1.73 ± 0.27

FT3 (pmol/L)

G1: 5.25 ± 0.57

G2: 5.14 ± 0.62

G3: 5.14 ± 0.62

G4: 5.17 ± 0.56

T4 (nmol/L)

G1: 86.5 ± 17.3

G2: 87.7 ± 18.1

G3: 85.6 ± 15.9

G4: 82.7 ± 15.8

FT4 (pmol/L)

G1: 12.2 ± 2.1

G2: 11.8 ± 1.6

G3: 12.0 ± 1.8

G4: 11.6 ± 1.9

T3:T4 (x10 ⁻² )

G1: 2.13 ± 0.43

G2: 2.12 ± 0.40

G3: 2.16 ± 0.50

G4: 2.14 ± 0.44

FT3:FT4

G1: 0.44 ± 0.08

G2: 0.44 ± 0.06

G3: 0.44 ± 0.08

G4: 0.45 ± 0.07

TSH (mU/L)

G1: 1.17 ± 0.66

G2: 1.24 ± 0.73

G3: 1.20 ± 0.61

G4: 1.21 ± 0.61

T3 (nmol/L)

G1: 1.79 ± 0.23

G2: 1.78 ± 0.22

G3: 1.80 ± 0.47

G4: 1.72 ± 0.25

Adj p = 0.56*

FT3 (pmol/L)

G1: 5.25 ± 0.61

G2: 5.15 ± 0.65

G3: 5.22 ± 0.55

G4: 5.17 ± 0.59

Adj p = 0.45*

T4 (nmol/L)

G1: 87.2 ± 18.0

G2: 87.0 ± 16.4

G3: 83.5 ± 14.5

G4: 81.6 ± 14.4

Adj p = 0.10*

FT4 (pmol/L)

G1: 12.1 ± 2.1

G2: 11.9 ± 1.6

G3: 11.9 ± 1.8

G4: 11.6 ± 1.7

Adj p = 0.92*

T3:T4 (× 10 ⁻² )

G1: 2.12 ± 0.41

G2: 2.09 ± 0.37

G3: 2.19 ± 0.46

G4: 2.15 ± 0.43

Adj p = 0.37*

FT3:FT4

G1: 0.44 ± 0.09

G2: 0.44 ± 0.07

G3: 0.45 ± 0.08

G4: 0.45 ± 0.07

Adj p = 0.41*

TSH (mU/L)

G1: 1.23 ± 0.72

G2: 1.23 ± 0.70

G3: 1.27 ± 0.69

G4: 1.18 ± 0.69

Adj p = 0.24*

*Between‐groups comparisons (ANCOVA; adjusted for baseline value, sex, age, and clinic location)

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)

Plasma levels of FT3, FT4, FT3:FT4, TSH

FT3 (pmol/L, median (IQR))

G1: 5.44 (0.77)

G2: 5.56 (0.71)

G3: 5.54 (0.68)

G4: 5.56 (0.83)

FT4 (pmol/L,

median (IQR))

G1: 12.88 (2.67)

G2: 13.06 (2.8)

G3: 13.43 (2.28)

G4: 13.43 (2.38)

FT3:FT4 (median, IQR))

G1: 0.43 (0.07)

G2: 0.43 (0.10)

G3: 0.42 (0.07)

G4: 0.42 (0.07)

TSH (mU/L, median (IQR))

G1: 1.21 (0.81)

G2: 1.28 (0.94)

G3: 1.14 (0.95)

G4: 1.18 (0.89)

FT3 (pmol/L, median (IQR))

G1: 5.54 (0.95)

G2: 5.59 (0.71)

G3: 5.58 (0.78)

G4: 5.53 (0.78)

FT4 (pmol/L, median (IQR))

G1: 13.32 (3.07)

G2: 13.52 (2.88)

G3: 13.24 (2.08)

G4: 13.25 (2.12)

FT3:FT4 (median, IQR))

G1: 0.42 (0.09)

G2: 0.42 (0.09)

G3: 0.42 (0.07)

G4: 0.42 (0.08)

TSH (mU/L, median (IQR))

G1: 1.22 (1.02)

G2: 1.17 (0.79)

G3: 1.32 (0.84)

G4: 1.06 (0.85)

Carvalho et al. (2015)

Brazil

RCT

G1, placebo: 45/42

G2, 227.5 μg Se/day: 44/35

Duration: 90 d

Aged 40–80 yr; with dyslipidemia and hypertension and treated for both conditions in the previous 3 mo; TSH within reference range (0.45–4.50 μUI/mL) and FT4 within reference range (0.70–1.48 ng/dL); no history of thyroid disease or thyroid medication use; no chronic renal failure; not using supplements containing > 20 μg Se/day; no excessive consumption of Brazil nuts; not having plasma Se levels > 125 μg/L; not being current smokers; not having been in a rigorous exercise/ weight‐reduction program in the previous 3 mo

Sex (% F): 44.2

Age (yr): 60.05 ± 10.27

BMI (kg/m ² ): 29.54 ± 5.60

Ethnicity: NR

Plasma Se (μg/L)

G1: 86.6 ± 17.2

G2: 88.7 ± 15.3

Se intake: NR

13 g/day partially defatted Brazil nut flour (227.5 μg of Se/d) vs 11 g/day of artificially flavoured dyed cassava flour as placebo (0.07 μg Se/d)

Plasma Se at 90 d follow up, μg/L

G1: 92.7 ± 16.8

G2: 169.5 ± 46.5

Plasma levels of FT3, FT4, TSH

Change from baseline

FT3 (pg/mL)

G1: −0.1 ± 0.4

G2: 0.1 ± 1.1

p = 0.030, for intragroup differences in G1, compared to baseline values

NS, for intragroup differences in G2 or intergroup differences at end of trial

FT4 (ng/dL)

G1: −0.1 ± 0.1 G2: 0.1 ± 0.6

NS, for intragroup differences in G1 and G2, or intergroup differences at end of trial

TSH (μUI/mL)

G1: −0.2 ± 0.9

G2: 0.2 ± 1.8

NS, for intragroup differences in G1 and G2.

p = 0.06 for intergroup differences at end of trial

Thomson et al. (2009)

New Zealand

RCT

G1, placebo: 25/24

G2, 100 Se μg/d: 25/25

Duration: 12 wk

Aged 60–80 yr; noninstitutionalised, free from cancer, diabetes, or cardiovascular disease; not using medications for thyroid function or with any known thyroid problems; not taking supplements containing Se or iodine.

Sex (% F): 55

Age (yr): 72.4 ± 4.8

BMI (kg/m ² ): 26.8 ± 5.8

Ethnicity: NR

Plasma Se (μmol/L)

G1: 1.23 ± 0.29

G2: 1.23 ± 0.31

Se intake: NR

L‐Selenomethionine (100 Se μg/d) vs placebo

Adherence: 90% of consuming all pills and 10% consuming between 97% and 99% pills.

Plasma levels of FT3, FT4, FT3:FT4, TSH

FT3 (pmol/L)

G1: 4.85 ± 0.47

G2: 4.70 ± 0.46

FT4 (pmol/L)

G1: 14.7 ± 2.0

G2: 14.0 ± 2.0

FT3:FT4 (median, IQR))

G1: 0.33 (0.31, 0.37)

G2: 0.34 (0.30, 0.39)

TSH (mIU/L, median (IQR))

G1: 2.35 (1.59, 3.41)

G2: 2.58 (1.76, 3.23)

Change from baseline

FT3 (geometric mean (95% CI))

G1: −0.10 (20.27, 0.08), p = 0.267*

G2: 0.15 (20.02, 0.31), p = 0.080*

FT4 (geometric mean (95% CI))

G1: −0.16 (20.65, 0.33), p = 0.521*

G2: 0.04 (20.43, 0.51), p = 0.881*

*Random‐coefficients mixed model, adjusted for age, sex, BMI, baseline plasma Se, medication use, and supplement use

Thomson et al. (2005)

Study 3: Dunedin smokers

New Zealand

RCT

G1, placebo: 30

G2, 100 μg Se/d: 30

Duration: 20 wk

Aged 19–52 yr; smokers; whole blood Se concentration < 1.0 mmol/L, or whole blood Se concentration between 1.0–1.2 mmol/L and whole blood glutathione peroxidase activities < 20 units/g Hb

Sex (% F): 50

Age (yr): 19–52

BMI (kg/m ² ): NR

Ethnicity: NR

Plasma Se (μmol/L)

G1: 0.99 ± 0.15

G2: 0.97 ± 0.14

Se intake: NR

L‐Selenomethionine (100 μg Se/day) vs placebo

Adherence: NR

Plasma levels of T3, T4, TSH

T4 (μmol/L)

G1: 99 ± 31

G2: 106 ± 36

T3:T4

G1: 0.021 ± 0.009

G2: 0.022 ± 0.008

TSH NR

T4 (μmol/L)

G1: 91 ± 32

G2: 98 ± 33

p = NS

T3:T4

G1: 0.020 ± 0.007

G2: 0.023 ± 0.008

p = NS

TSH NR

Thomson et al. (2005)

Study 5: Dunedin residents

New Zealand

RCT

G1, placebo: 86

G2, 200 μg Se/d: 86

Duration: 20 wk

Aged 18–65 years, healthy

Sex (% F): 66.28

Age (yr): 18–65

BMI (kg/m ² ): NR

Ethnicity: NR

Plasma Se (μmol/L)

G1: 1.06 ± 0.23

G2: 1.14 ± 0.28

Se intake: NR

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

Adherence: NR

Plasma levels of T3, T4, TSH

T4 (μmol/L)

G1: 89 ± 18

G2: 88 ± 23

T3:T4

G1: 0.018 ± 0.003

G2: 0.019 ± 0.006

TSH NR

T4 (μmol/L)

G1: 88 ± 23

G2: 84 ± 22

p = NS

T3:T4

G1: 0.018 ± 0.005

G2: 0.018 ± 0.004

p = NS

TSH NR

Hawkes et al. (2008)

USA

RCT

G1, placebo: 20

G2, 300 μg Se/d: 22

Duration: 48 wk

No hypertension, diabetes, sexually transmitted disease, or cancer; clinically normal blood count, blood chemistries and thyrotropin; no smokers; no use of Se shampoos, Se supplements > 50 mg/d, thyroid medications, weight loss drugs, or anabolic steroids; not > 10 lb weight change within last 6 mo; no exercise or physical training in excess of 3 × 1‐h sessions per wk.

Sex: M

Age (yr): 18–45

BW (kg):

G1: 77.4 ± 11.9

G2: 76.3 ± 9.9

Ethnicity: NR

Plasma Se: NR

Se intake (3‐d diet record): 135 ± 57 μg/d

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

Adherence, pills count (%): 93 ± 5.3

Plasma levels of T3, FT3, T4, FT4, TSH

T3 (nmol/L)

G1: 1.90 ± 0.38

G2: 2.17 ± 0.43

FT3 (pmol/L)

G1: 41 ± 11

G2: 45 ± 7.5

T4 (nmol/L)

G1: 91 ± 17

G2: 94 ± 17

FT4 (nmol/L)

G1: 18 ± 2.7

G2: 18 ± 2.7

TSH (mU/L)

G1: 2.30 ± 1.31

G2: 2.10 ± 0.85

T3 (nmol/L)

G1: 1.77 ± 0.28

G2: 1.98 ± 0.35

p = NS

FT3 (pmol/L)

G1: 39 ± 7.5

G2: 45 ± 17

p = NS

T4 (nmol/L)

G1: 92 ± 18

G2: 92 ± 22

p = NS

FT4 (nmol/L)

G1: 18 ± 3.0

G2: 18 ± 2.2

p = NS

TSH (mU/L)

G1: 2.16 ± 1.11

G2: 2.11 ± 1.10

p = NS

Hawkes and Keim (2003)

USA

RCT

G1, low Se diet: 6/6

G2, high Se diet: 6/5

Duration: 99 d

Healthy; BW for height 125% of ideal; no use of Se supplements or Se‐containing shampoos; normal ECG, blood cell counts, clinical chemistries or semen analysis; no HIV infection; no use of illegal drugs; no use of tobacco or alcohol; no use of medications; no history of psychiatric illness, thyroid or heart disease, syphilis, hepatitis, diabetes, hypertension or hyperlipidaemia.

Sex: M

Age (yr): 20–45

BW (kg):

G1: 74.9 ± 9.8

G2: 73.5 ± 12.6

Ethnicity: NR

Plasma Se (μg/L)*

G1: 118 ± 8

G2: 107 ± 19

Se intake: NR

Stabilisation period: 47 μg/day of Se for 21‐d; then randomised to receive foods with naturally high (297 μg/d) or low (14 μg/d) Se content; diet controlled in metabolic research unit.

Plasma levels of T3, T4, TSH

T3 (nmol/L)*

G1: 1.57 ± 0.25

G2: 1.82 ± 0.36

T4 (nmol/L)*

G1: 118 ± 26

G2: 113 ± 15

TSH (mU/L)*

G1: 1.69 ± 0.30

G2: 2.25 ± 0.81

* Values at 21‐d (end of stabilisation period)

T3 (nmol/L)

G1: 1.64 ± 0.16

G2: 1.57 ± 0.07

p Se = 0.013; p time = NS; p Se × time = 0.048^#

T4 (nmol/L)

G1: 90.3 ± 6.6

G2: 86.8 ± 12.7

p Se = NS; p time = 0.033; p Se × time model = NS^#

TSH (mU/L)

G1: 1.77 ± 0.46

G2: 2.96 ± 1.05

p Se = NS; p time = 0.011; p Se × time = 0.031^#

^#Repeated‐measures ANOVA, controlling for baseline values

Duffield and Thomson (1999)

New Zealand

RCT

G1, placebo: 10

G2, 10 Se μg/d: 10

G3, 20 Se μg/d: 11

G4, 30 Se μg/d: 10

G5, 40 Se μg/d: 11

Duration: 20 wk

New Zealand residents;

whole‐blood Se concentrations < 1.26 mmol/L

Sex (% F): 67.31

Age (yr): 19–59 y

BW (kg):

G1: 78.5

G2: 66.4

G3: 76.6

G4: 79.4

G5: 67.8

Ethnicity: NR

Plasma Se (μmol/L)

G1: 0.783

G2: 0.806

G3: 0.846

G4: 0.869

G5: 0.809

Se intake (μg/day)

3‐d duplicate diets: 29 ± 13

3‐d diet records: 28 ± 15

L‐selenomethionine (10 Se μg/day, 20 Se μg/day, 30 Se μg/day or 40 Se μg/day) vs placebo

Adherence (assessed by pill counts) NR

Increase in whole‐blood Se at 20 kw follow up vs baseline, % (mean)

G1: +4

G2: +9

G3: +9

G4: +7

G5: +13

Plasma levels of T4

T4 (nmol/L)

G1: 95 ± 32

G2: 108 ± 21

G3: 97 ± 15

G4: 97 ± 18

G5: 95 ± 23

T4 (nmol/L)

G1: 99 ± 30

G2: 93 ± 10*

G3: 88 ± 15

G4: 90 ± 17

G5: 89 ± 19

G2‐G5 (combined): 89 ± 15*

*Significantly different from week 0 after adjustment for baseline value, p < 0.05

Olivieri et al. (1995)

Italy

RCT

G1, placebo: 20/17

G2, 100 Se μg/d: 20/19

Duration: 3 mo

No nutritional disturbances, thyroid or gastrointestinal diseases that could influence thyroid hormones or Se status; not taking supplements.

Sex (% F): 77.8

Age (yr): 85 ± 7

Ethnicity: Caucasian

Serum Se (μmol/L)

G1: 0.79 ± 0.18

G2: 0.83 ± 0.13

Se intake: NR

Sodium selenite (100 Se μg/d) vs placebo

Adherence: tablets given during breakfast over the supervision of a nurse.

Serum Se increased by 61% in the supplemented participants vs no change in the control group

Plasma levels of T3, T4, FT4, T3:T4, TSH

T3 (nmol/L)

G1: 1.1 ± 0.17

G2: 1.08 ± 0.14

T4 (nmol/L)

G1: 70 ± 13

G2: 67 ± 9

FT4 (pmol/L)

G1: 9.99 ± 2.2

G2: 9.4 ± 1.5

T3:T4

G1: 0.016 ± 0.003

G2: 0.016 ± 0.002

TSH (mU/L)

G1: 1.14 ± 0.51

G2: 1.2 ± 0.5

T3 (nmol/L)

G1: 1.1 ± 0.09

G2: 0.99 ± 0.2

T4 (nmol/L)

G1: 68.5 ± 10.4

G2: 62 ± 10*

FT4 (pmol/L)

G1: 10 ± 1.65 G2: 9.3 ± 2

T3:T4

G1: 0.015 ± 0.002

G2: 0.016 ± 0.003

TSH (mU/L)

G1: 0.99 ± 0.71

G2: 1.18 ± 0.58

*paired Student t‐test: significant difference between values at baseline vs end of trial (p < 0.05).

CI: confidence interval; d: day; BMI: Body mass index; BW: body weight; DK: Denmark; ECG: electrocardiogram; ERMS: error root mean square; F: females; Gx: group x; HIV: human immunodeficiency virus; M: males; mo: month; NR: not reported; NS: not significant; PRECISE: PREvention of Cancer by Intervention with Selenium; RCT: randomised controlled trial; Se: selenium; SWOG: Southwest Oncology Group; T3: triiodothyronine; T4: thyroxine; TSH: thyroid‐stimulating hormone; FT3: free triiodothyronine; FT4: free thyroxine; T3:T4: triiodothyronine: thyroxine ratio; UK: United Kingdom; 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.