Re‐evaluation of the existing health‐based guidance values for copper and exposure assessment from all sources

View full-text article in PMC

. 2023 Jan 17;21(1):e07728. doi: 10.2903/j.efsa.2023.7728

Reference	Study population	Duration of study	Form of copper doses	Method	Copper absorption/excretion/retention	Biochemical markers of copper status
(Turnlund, 1989 ; Turnlund et al., 1990 )	11 young M (22–35 years)	P1: 24 days P2: 42 days P3: 24 days	P1: 1.7 mg/day total Cu (⁶⁵Cu fed on day 13) P2: 0.8 mg/day total Cu (⁶⁵Cu fed on days 7 and 8 and days 31 and 32) P3: 7.5 mg/day total Cu (⁶⁵Cu fed on day 13) Food and formula in the diet contained 0.4 mg Cu; additional Cu provided as CuSO₄ (liquid formula)	Complete urine and stool collections were made throughout the study Cu absorption and retention (using ⁶⁵Cu)	Mean ± SEM (range) % ⁶⁵ Cu absorption P1: 36.3 ± 1.3 (30.2, 42.1) P2 (early; late): 56.2 ± 1.1 (48.9, 61.3); 55.0 ± 1.5 (46.0, 60.3) P3: 12.4 ± 0.9 (7.4, 16.4) Cu absorption (mg/day) P1: 0.61 ± 0.022 P2 (early; late): 0.441 ± 0.009; 0.43 ± 0.012 P3: 0.93 ± 0.068 Endogenous faecal loss (mg/day) P1: 0.61 (average day 7 to day 24 of P1) P2 (early; late): 0.36 (average day 7 to day 24 of P2); 0.33 (average day 25 to day 42 of P2) P3: 0.97 (average day 7 to day 24 of P3) Retention (mg/day) (average over each metabolic period) P1: 0.167 ± 0.40 (–0.046, 0.308) P2: 0.002 ± 0.034 (–0.255, 0.125) P3: 0.941 ± 0.160 (0.128, 1.97) P3: balance was strongly positive at first and decreased linearly with time (became negative at the end of the period); the 24‐day period was insufficient for men to equilibrate.	Plasma Cu, CP and eSOD: no effect Salivary Cu: no effect
(Harvey et al., 2003 )	12 M (20–59 years)	P1: 8 weeks P2: 8 weeks P3: 8 weeks ≥ 4 weeks washout between periods	P1: 1.6 mg/day total Cu (⁶⁵Cu administered orally on day 42) P2: 0.7 mg/day total Cu (⁶⁵Cu administered orally on day 42) P3: 6.0 mg/day total Cu (⁶⁵Cu administered orally on day 42) During all periods, diet contained 0.7 mg/day Cu; additional Cu provided as CuSO₄ (liquid formula)	Cu absorption and retention (using ⁶⁵Cu) Apparent Cu absorption: (labelled Cu dose–labelled Cu in faeces)/labelled Cu dose True absorption = Apparent Cu absorption corrected for endogenous Cu loss Retention = unlabelled dose, i.e. unlabelled Cu in faeces	Mean ± SD % ⁶⁵ Cu apparent/true absorption (%) P1: 42 ± 15/45 ± 14 P2: 41 ± 12/48 ± 13 P3: 45 ± 13/48 ± 11 Cu apparent/true absorption (mg) P1: 1.27 ± 0.44/1.36 ± 0.41 P2: 1.23 ± 0.35/1.45 ± 0.39 P3: 1.34 ± 0.38/1.45 ± 0.33 Faecal Cu (mg/day) (unlabelled Cu recovered 14 days after label administration) P1: 1.6 ± 0.31 P2: 0.83 ± 0.32 P3: 5.25 ± 1.05 ⁶⁵ Cu endogenous loss (%) P1: 38 ± 20 P2: 30 ± 15 P3: 40 ± 11 Total endogenous loss (slow and fast pools) (mg/day) P1: 0.81 ± 0.16 P2: 0.45 ± 0.25 P3: 2.46 ± 1.11 Retention (mg/day) (at the end of the period) P1: 0.00 ± 0.31 P2: −0.13 ± 0.32 P3: 0.75 ± 1.05	Plasma Cu, CP and eSOD: no effect
(Turnlund et al., 1998 )	11 M (mean 26 ± 4 years)	P1: 24 days P2: 42 days P3: 24 days	P1: 0.66 mg/day (diet copper was replaced with ⁶⁵Cu in six subjects on days 13 and 14 and 0.34 mg was administered intravenously to five subjects on day 13) P2: 0.38 mg/day, basal dietary content with no added copper (0.2 mg of ⁶⁵Cu was added to the diet of six subjects on days 31 and 32 and days 55 and 56, and 0.34 mg was administered intravenously to five subjects on day 55) P3: 2.49 mg/day (copper was replaced with ⁶⁵Cu in the diet given to six subjects on days 79–80 and 0.34 mg was administered intravenously to five subjects on day 79)	Cu absorption, excretion and retention (using ⁶⁵Cu) Apparent Cu absorption = amount of ⁶⁵Cu fed – amount of ⁶⁵Cu recovered in the stools in a 12‐d period after the feeding True absorption = Apparent Cu absorption corrected by the fraction of infused ⁶⁵Cu excreted over the same time period Retention = average Cu intake – average faecal Cu (averages of entire metabolic period)	Mean % Cu apparent/true absorption (%) P1: 54/73 P2: 67/77 P3: 44/66 Cu apparent/true absorption (mg/day) P1: 0.35/0.48 P2: 0.26/0.29 P3: 1.08/1.64 Faecal ⁶⁵ Cu (% of dose of infused ⁶⁵Cu excreted in the 12 days after infusion) P1: 26 P2: 12 P3: 34 Faecal Cu (mg/day) P1: 0.65 P2: 0.33 P3: 2.17 Endogenous loss (mg/day) P1: 0.47 P2: 0.24 P3: 1.33 Retention (mg/day) (average over entire metabolic period) P1: −0.13 P2: −0.015 P3: 0.511 (positive balance in first 6 days decreased rapidly afterwards; equilibrium was reached at the end of the period; see text)	None
(Turnlund et al., 2005 )	9 M (26–49 years)	P1: 18 days P2: 129 days P3: 18 days	P1: 1.6 mg/day (⁶³Cu administered orally to three subjects and intravenously to six subjects on day 7) P2: usual diet + 7 mg/day Cu supplement P3: 7.8 mg/day (⁶³Cu administered orally to three subjects and intravenously to six subjects on day 7) During periods 1 and 3, diet contained 1.6 mg/day Cu; additional Cu provided as CuSO₄ (liquid formula) During P2, subjects consumed supplements that provided 7 mg Cu/day as copper sulfate	Complete urine and stool collections were made throughout P1 and P3 Apparent Cu absorption = amount of ⁶³Cu fed – amount of ⁶³Cu recovered in the stools in a 12‐d period after the feeding True Cu absorption = apparent Cu absorption corrected by the fraction of infused ⁶³Cu excreted over the same time period. Total endogenous gastrointestinal losses = total faecal Cu – unabsorbed dietary Cu Cu retention = average Cu intake – average faecal and urinary Cu (averages of the last 12 days of each metabolic period)	Mean % Cu apparent/true absorption (%) P1: 29/40 P3: 16/29 Cu apparent/true absorption (mg/day) P1: 0.48/0.65 P3: 1.2/2.2 Faecal ⁶³ Cu (% of dose of infused ⁶³Cu excreted in the 12 days after infusion) P1: 27 P3: 46 Faecal Cu (mg/day) P1: 1.6 P3: 7.1 Endogenous loss (mg/day) P1: 0.58 P3: 1.56 Urinary ⁶³ Cu (% of dose of infused ⁶³Cu excreted in the 12 days after infusion) P1: 2.1 P3: 1.3 Urinary Cu (mg/day) P1: 0.0203 ± 0.0008 P3: 0.0256 ± 0.0011 Hair Cu (mg/day) P1: 0.0092 ± 0.0031 P3: 0.0211 ± 0.0029 Retention (mg/day) (average for the last 12 days of each metabolic period) P1: 0.06 P3: 0.67	eSOD: ↑ P3 vs P1 (P1: 1,065 r ± 47; P3: 1,206 r ± 24 U/g Hb) Plasma benzylamine oxidase activity: ↑ P3 vs P1 (P1: 283 ± 25; P3: 377 ± 31 U/L) CP activity: ↑ P3 vs P1 (P1: 107 ± 3; P3: 116 ± 5 U/L) Plasma Cu: no effect

Reference

Study population

Duration of study

Form of copper doses

Method

Copper absorption/excretion/retention

Biochemical markers of copper status

(Turnlund, 1989 ; Turnlund et al., 1990 )

11 young M

(22–35 years)

P1: 24 days

P2: 42 days

P3: 24 days

P1: 1.7 mg/day total Cu (⁶⁵Cu fed on day 13)

P2: 0.8 mg/day total Cu (⁶⁵Cu fed on days 7 and 8 and days 31 and 32)

P3: 7.5 mg/day total Cu (⁶⁵Cu fed on day 13)

Food and formula in the diet contained 0.4 mg Cu; additional Cu provided as CuSO₄ (liquid formula)

Complete urine and stool collections were made throughout the study

Cu absorption and retention (using ⁶⁵Cu)

Mean ± SEM (range)

% ⁶⁵ Cu absorption

P1: 36.3 ± 1.3 (30.2, 42.1)

P2 (early; late): 56.2 ± 1.1 (48.9, 61.3); 55.0 ± 1.5 (46.0, 60.3)

P3: 12.4 ± 0.9 (7.4, 16.4)

Cu absorption (mg/day)

P1: 0.61 ± 0.022

P2 (early; late): 0.441 ± 0.009; 0.43 ± 0.012

P3: 0.93 ± 0.068

Endogenous faecal loss (mg/day)

P1: 0.61 (average day 7 to day 24 of P1)

P2 (early; late): 0.36 (average day 7 to day 24 of P2); 0.33 (average day 25 to day 42 of P2)

P3: 0.97 (average day 7 to day 24 of P3)

Retention (mg/day) (average over each metabolic period)

P1: 0.167 ± 0.40 (–0.046, 0.308)

P2: 0.002 ± 0.034 (–0.255, 0.125)

P3: 0.941 ± 0.160 (0.128, 1.97)

P3: balance was strongly positive at first and decreased linearly with time (became negative at the end of the period); the 24‐day period was insufficient for men to equilibrate.

Plasma Cu, CP and eSOD: no effect

Salivary Cu: no effect

(Harvey et al., 2003 )

12 M (20–59 years)

P1: 8 weeks

P2: 8 weeks

P3: 8 weeks

≥ 4 weeks washout between periods

P1: 1.6 mg/day total Cu (⁶⁵Cu administered orally on day 42)

P2: 0.7 mg/day total Cu (⁶⁵Cu administered orally on day 42)

P3: 6.0 mg/day total Cu (⁶⁵Cu administered orally on day 42)

During all periods, diet contained 0.7 mg/day Cu; additional Cu provided as CuSO₄ (liquid formula)

Cu absorption and retention (using ⁶⁵Cu)

Apparent Cu absorption: (labelled Cu dose–labelled Cu in faeces)/labelled Cu dose

True absorption = Apparent Cu absorption corrected for endogenous Cu loss

Retention = unlabelled dose, i.e. unlabelled Cu in faeces

Mean ± SD

% ⁶⁵ Cu apparent/true absorption (%)

P1: 42 ± 15/45 ± 14

P2: 41 ± 12/48 ± 13

P3: 45 ± 13/48 ± 11

Cu apparent/true absorption (mg)

P1: 1.27 ± 0.44/1.36 ± 0.41

P2: 1.23 ± 0.35/1.45 ± 0.39

P3: 1.34 ± 0.38/1.45 ± 0.33

Faecal Cu (mg/day) (unlabelled Cu recovered 14 days after label administration)

P1: 1.6 ± 0.31

P2: 0.83 ± 0.32

P3: 5.25 ± 1.05

⁶⁵ Cu endogenous loss (%)

P1: 38 ± 20

P2: 30 ± 15

P3: 40 ± 11

Total endogenous loss (slow and fast pools) (mg/day)

P1: 0.81 ± 0.16

P2: 0.45 ± 0.25

P3: 2.46 ± 1.11

Retention (mg/day) (at the end of the period)

P1: 0.00 ± 0.31

P2: −0.13 ± 0.32

P3: 0.75 ± 1.05

Plasma Cu, CP and eSOD: no effect

(Turnlund et al., 1998 )

11 M (mean 26 ± 4 years)

P1: 24 days

P2: 42 days

P3: 24 days

P1: 0.66 mg/day (diet copper was replaced with ⁶⁵Cu in six subjects on days 13 and 14 and 0.34 mg was administered intravenously to five subjects on day 13)

P2: 0.38 mg/day, basal dietary content with no added copper (0.2 mg of ⁶⁵Cu was added to the diet of six subjects on days 31 and 32 and days 55 and 56, and 0.34 mg was administered intravenously to five subjects on day 55)

P3: 2.49 mg/day (copper was replaced with ⁶⁵Cu in the diet given to six subjects on days 79–80 and 0.34 mg was administered intravenously to five subjects on day 79)

Cu absorption, excretion and retention (using ⁶⁵Cu)

Apparent Cu absorption = amount of ⁶⁵Cu fed – amount of ⁶⁵Cu recovered in the stools in a 12‐d period after the feeding

True absorption = Apparent Cu absorption corrected by the fraction of infused ⁶⁵Cu excreted over the same time period

Retention = average Cu intake – average faecal Cu (averages of entire metabolic period)

Mean

% Cu apparent/true absorption (%)

P1: 54/73

P2: 67/77

P3: 44/66

Cu apparent/true absorption (mg/day)

P1: 0.35/0.48

P2: 0.26/0.29

P3: 1.08/1.64

Faecal ⁶⁵ Cu (% of dose of infused ⁶⁵Cu excreted in the 12 days after infusion)

P1: 26

P2: 12

P3: 34

Faecal Cu (mg/day)

P1: 0.65

P2: 0.33

P3: 2.17

Endogenous loss (mg/day)

P1: 0.47

P2: 0.24

P3: 1.33

Retention (mg/day) (average over entire metabolic period)

P1: −0.13

P2: −0.015

P3: 0.511 (positive balance in first 6 days decreased rapidly afterwards; equilibrium was reached at the end of the period; see text)

None

(Turnlund et al., 2005 )

9 M

(26–49 years)

P1: 18 days

P2: 129 days

P3: 18 days

P1: 1.6 mg/day (⁶³Cu administered orally to three subjects and intravenously to six subjects on day 7)

P2: usual diet + 7 mg/day Cu supplement

P3: 7.8 mg/day (⁶³Cu administered orally to three subjects and intravenously to six subjects on day 7)

During periods 1 and 3, diet contained 1.6 mg/day Cu; additional Cu provided as CuSO₄ (liquid formula)

During P2, subjects consumed supplements that provided 7 mg Cu/day as copper sulfate

Complete urine and stool collections were made throughout P1 and P3

Apparent Cu absorption = amount of ⁶³Cu fed – amount of ⁶³Cu recovered in the stools in a 12‐d period after the feeding

True Cu absorption = apparent Cu absorption corrected by the fraction of infused ⁶³Cu excreted over the same time period.

Total endogenous gastrointestinal losses = total faecal Cu – unabsorbed dietary Cu

Cu retention = average Cu intake – average faecal and urinary Cu (averages of the last 12 days of each metabolic period)

Mean

% Cu apparent/true absorption (%)

P1: 29/40

P3: 16/29

Cu apparent/true absorption (mg/day)

P1: 0.48/0.65

P3: 1.2/2.2

Faecal ⁶³ Cu (% of dose of infused ⁶³Cu excreted in the 12 days after infusion)

P1: 27

P3: 46

Faecal Cu (mg/day)

P1: 1.6

P3: 7.1

Endogenous loss (mg/day)

P1: 0.58

P3: 1.56

Urinary ⁶³ Cu (% of dose of infused ⁶³Cu excreted in the 12 days after infusion)

P1: 2.1

P3: 1.3

Urinary Cu (mg/day)

P1: 0.0203 ± 0.0008

P3: 0.0256 ± 0.0011

Hair Cu (mg/day)

P1: 0.0092 ± 0.0031

P3: 0.0211 ± 0.0029

Retention (mg/day) (average for the last 12 days of each metabolic period)

P1: 0.06

P3: 0.67

eSOD:

↑ P3 vs P1 (P1: 1,065 r ± 47; P3: 1,206 r ± 24 U/g Hb)

Plasma benzylamine oxidase activity:

↑ P3 vs P1 (P1: 283 ± 25; P3: 377 ± 31 U/L)

CP activity:

↑ P3 vs P1 (P1: 107 ± 3; P3: 116 ± 5 U/L)

Plasma Cu: no effect

↑: significant increase; CP: caeruloplasmin; eSOD: erythrocyte superoxide dismutase; Hb: haemoglobin; M: males; SD: standard deviation; SEM: standard error of the mean.