Copper

Clinical Summary

Copper is an essential trace mineral required as a cofactor for >20 cuproenzymes governing iron metabolism (ceruloplasmin), antioxidant defense (Cu/Zn-SOD1), mitochondrial energy production (cytochrome c oxidase), connective tissue integrity (lysyl oxidase), neurotransmitter synthesis (dopamine β-hydroxylase), melanin production (tyrosinase), and immune function.

The evidence base for copper is overwhelmingly about deficiency correction, not supplementation enhancement. In copper-replete individuals, there is essentially zero RCT evidence that additional copper improves any health outcome. The compound becomes clinically important in specific at-risk populations: post-bariatric surgery (10-20% deficiency rate within 1-5 years per PMID 39755772), high-dose Zinc users (>50 mg/d induces copper depletion via metallothionein), elderly on PPIs, celiac disease, IBD, and TPN-dependent patients.

Body copper is tightly homeostatically regulated: CTR1 controls intestinal absorption, ATP7A exports copper to blood, ATP7B loads copper into ceruloplasmin and excretes excess via bile. Mutations in ATP7A cause Menkes disease (copper deficiency); mutations in ATP7B cause Wilson disease (copper toxicity). The therapeutic index is wide (UL:RDA = 11:1), making copper one of the safer minerals to supplement at physiologic doses.

Emerging research (2024-2026): cuproptosis (copper-dependent cell death) as a major oncology research axis; Cu/Zn ratio as a cross-disease biomarker (ASD, cardiovascular, thyroid); meta-analysis confirming dietary copper → bone health association (PMID 41361655); elevated serum copper associated with major depressive disorder (PMID 41263185, meta-analysis); copper deficiency impairs oligodendrocyte maturation in ASD model (PMID 41920999, Sci Adv, Japan).

Indications & Evidence

Reading this table: Stars = evidence volume. Type = causal relationship (see legend). BH = Bradford Hill criteria met (/9). Safety = FAERS/trial signals for THIS specific indication. One row = one decision.

Hard rule: Star rating cannot exceed the causal taxonomy ceiling for its Type.

Type codes: DC=Direct causation | PC=Probable | UCC=Unreplicated causal | BC=Biomarker correlation | SE=Surrogate endpoint | ME=Mechanistic extrapolation | AHE=Animal→human | OA=Observational | RC=Reverse causation | CF=Confounded | FA=Folk/anecdotal | NE=No evidence BH: Bradford Hill criteria met (of 9). 7-9=strong causal | 5-6=moderate | 3-4=weak | 1-2=speculative | 0=none Safety flags: -- No signals | MON Monitor (known AEs, manageable) | WARN FAERS or trial safety signal — see Safety section | AVOID Contraindicated for this specific indication

Star rating legend: 5/5 Multiple large RCTs + meta-analyses | 4/5 Several human RCTs or extensive case series | 3/5 Some human data or strong mechanistic | 2/5 Animal/very limited human | 1/5 None/debunked

Prescribing

Dosing Table

Formulation Table

Condition-Specific Protocols

Copper Deficiency Protocol

Evidence: 5/5 | PMIDs: 29959467, 6410510, 31209935

Phase 1: Identification & Initiation (Week 1-2)

• Confirm: serum copper <70 µg/dL AND/OR ceruloplasmin <20 mg/dL
• Rule out Wilson disease (low ceruloplasmin + HIGH urinary copper = Wilson, not deficiency)
• Start 2-4 mg/d copper gluconate or bisglycinate; add Vitamin C 100 mg for absorption
• Baseline labs: CBC, serum copper, ceruloplasmin, zinc, iron panel

Phase 2: Therapeutic (Weeks 3-12)

• Maintain 2-4 mg/d. Expect: neutrophil recovery 2-4 wk, hemoglobin +1-2 g/dL/mo
• Week 4: repeat CBC (expect ANC normalization, Hb rising)
• Week 12: full panel — serum copper, ceruloplasmin, CBC, zinc

Phase 3: Maintenance (Week 12+)

• Reduce to 1-2 mg/d once labs normalize
• Monitor serum copper + ceruloplasmin every 6-12 months
• Address root cause (zinc excess, malabsorption, bariatric)

Stop/Reassess: Serum copper >150 µg/dL, free copper >25 µg/dL, liver enzyme elevation

Post-Bariatric Surgery Protocol

Evidence: 5/5 | PMIDs: 39755772, 41353140, 41455456

Prevention: 2 mg/d copper bisglycinate started immediately post-surgery, lifelong If deficiency develops: Increase to 4-6 mg/d oral; consider IV 1-2 mg/d if no response at 8-12 wk Monitoring: Serum copper + ceruloplasmin every 6-12 months indefinitely Key risk factors: RYGB > OAGB > sleeve (deficiency rates decrease in that order per PMID 41353140) Neurological urgency: Copper deficiency myelopathy post-bariatric is increasingly reported (PMID 41455456, Taiwan); treat within 6 months for partial reversibility

Safety

Interactions Table

Contraindications

• Wilson disease — ABSOLUTE. ATP7B mutation → impaired biliary excretion → hepatic/neurological copper accumulation. Supplementation worsens disease. Prevalence: 1 in 30,000.
• Indian Childhood Cirrhosis / Idiopathic Copper Toxicosis — ABSOLUTE. Progressive hepatic copper accumulation.
• Cholestatic liver disease — RELATIVE. Impaired bile flow → reduced copper excretion. Check copper status first; avoid if elevated.
• Hemochromatosis — RELATIVE. Combined redox-active metals increase oxidative stress. Only supplement if deficiency documented.
• Severe renal impairment (GFR <30) — RELATIVE. Consider 50% dose reduction. Monitor q3-6mo.

Adverse Effects

Common (>1%): Nausea (5-15%, dose-dependent, sulfate > citrate > gluconate > bisglycinate), abdominal cramping (3-8%), metallic taste (2-5%), diarrhea (1-3%) Uncommon (0.1-1%): Vomiting (0.5-1%), headache (0.3-0.8%) Rare (<0.1%): Allergic reactions, liver enzyme elevation (chronic >10 mg/d only) Acute toxicity: >10-15 mg/kg single dose (severe GI, hemolysis, liver/kidney injury). Extremely rare with supplements. Chronic toxicity: >10 mg/d for months-years → hepatotoxicity, neurological damage. Wilson disease patients are the primary risk group.

FAERS Signal Table

Reading FAERS data: FAERS for copper is overwhelmingly noise from copper IUD (ParaGard) device malfunction reports. For oral copper supplement forms: copper gluconate has zero suspect-drug reports (all 292 reports are concomitant). Copper sulfate has one suspect report. This confirms the supplement FAERS noise pattern — copper supplements have an excellent safety profile at physiologic doses.

Monitoring Table

Special Populations

Renal Impairment

Hepatic Impairment

Synergies & Stacking

Individual Response Modifiers

Sex-Specific Considerations

Genetic Modifiers

Community & Anecdotal Evidence

Disclaimer: This section captures real-world user reports from online communities. None of this constitutes clinical evidence. N-sizes are approximate. Selection bias, placebo effect, and recall bias are inherent. Presented for completeness, not as medical guidance.

Dominant Sentiment

Mixed-to-positive across ~500+ reports reviewed (Reddit r/Supplements, r/Nootropics, r/longevity; LongeCity; Phoenix Rising ME/CFS forums; TikTok)

What Users Report

Community Dosing vs Clinical

Popular Stacks (Community)

Red Flags & Skepticism Notes

• MLM involvement: MitoSynergy markets a "copper 1" (cuprous niacin) complex at premium prices (~$30-50/mo vs $5-10/mo for standard copper). They promote the "copper 1 vs copper 2" distinction aggressively. The company removes negative feedback from their Facebook group. Trustpilot complaints include expired products, shipping issues, and oxidized product. The "copper 1 is bioavailable, copper 2 is toxic" claim is an oversimplification — all oral copper forms are reduced to Cu⁺ by intestinal Dcytb before CTR1 absorption regardless of starting oxidation state.
• Influencer concentration: TikTok gray hair reversal trend driven by many small creators, not a single influencer. Broad organic interest, not astroturfed.
• Astroturfing signals: Not detected for standard copper supplements. MitoSynergy has some aggressive marketing patterns but is a single niche brand.
• Commercial bias: Copper supplements are commodity-priced ($0.05-0.25/day). Low profit margins → low incentive for industry hype. The opposite concern is more valid: zinc supplement marketing rarely mentions the need for copper co-supplementation.

Folk vs Clinical Reality Check

Community experience aligns well with clinical data on one key point: copper supplementation helps people who are actually deficient, especially those on high-dose zinc. The energy and cognition improvements reported by deficient users match the biochemistry (cytochrome c oxidase, dopamine β-hydroxylase). Where community diverges from evidence: (1) gray hair reversal claims vastly exceed the evidence — tyrosinase requires copper, but oral supplementation restoring hair color has zero RCT support; (2) the "copper 1 vs copper 2" debate on LongeCity is chemically misleading, since intestinal reductases convert all dietary copper to Cu⁺ before absorption; (3) micro-dosing reports from ME/CFS forums (<200 mcg) are plausible for genuinely deficient individuals but cannot be generalized.

Deep Dive: Mechanisms & Research

Key Cuproenzymes and Clinical Translation:

Cuproptosis (2022-present): Copper-induced cell death via lipoylated TCA cycle protein aggregation has become a major oncology research axis with >500 publications since 2022. Disulfiram + copper combination therapy is in Phase 1-2 trials for sarcoma (NCT05210374) and metastatic breast cancer (NCT03323346). Not directly relevant to supplementation but informs copper's dual-edged biology.

Copper-ASD connection (2026): PMID 41920999 (Usui et al., Sci Adv, Japan) demonstrated copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy/mTOR suppression. Combined with Cu/Zn ratio imbalance data in ASD (PMID 41372683, reanalysis of 6 multinational studies), this opens a new research axis.

LRRK2-copper-COX assembly (2026): PMID 41621246 (Kim et al., Korea) showed LRRK2 controls cytochrome c oxidase assembly through regulation of mitochondrial copper chaperone redox status — a novel Parkinson's disease mechanism linking copper homeostasis to neurodegeneration.

Clinical Trials (from BioMCP / ClinicalTrials.gov)

Regulatory Status

• FDA: Oral copper supplements — dietary supplements under DSHEA (no NDA required). Cupric chloride injectable (NDA018960) — approved for TPN. Zycubo (copper histidinate, NDA211241, Sentynl Therapeutics) — approved January 2026 for Menkes disease (first FDA-approved disease-specific copper therapy).
• EMA: Cuprymina (copper-64 chloride) authorised as radiopharmaceutical precursor. No EMA-authorised oral copper supplements.
• Regulatory context: Oral copper has never needed drug approval because it's a commodity mineral available as a dietary supplement. The Zycubo approval for Menkes is a landmark — it validates copper replacement as a formal pharmaceutical therapy for genetic copper deficiency.

Ataraxia Verdict (as of 2026-04-16)

Evidence Classification (Mode 5: Evidence Classifier)

Hype Check (Mode 1: Fallacy Radar)

• Primary fallacy: Conflation of deficiency-correction evidence with supplementation-enhancement benefit. Nearly all 5/5 evidence is for reversing deficiency, not improving outcomes in copper-replete individuals.
• TikTok gray hair trend: Classic appeal to mechanism — tyrosinase requires copper, therefore copper supplements reverse graying. Missing step: oral supplementation in non-deficient individuals has never been shown to increase melanocyte copper above baseline.
• "Copper 1 vs Copper 2" (MitoSynergy): Misleading distinction. All dietary copper is reduced to Cu⁺ by intestinal ferrireductases before CTR1 absorption. The oxidation state of the supplement is irrelevant to absorption efficiency.
• No appeal to authority detected — copper research is spread across many independent groups.
• No cherry-picking pattern — the U-shaped risk curve (deficiency and excess both harmful) is consistently acknowledged in the literature.

Evidence Gaps

• Zero RCTs testing copper supplementation for any outcome in copper-replete individuals
• No head-to-head formulation comparison studies (gluconate vs bisglycinate vs sulfate) in humans
• Copper bioavailability estimates for chelated forms extrapolated from zinc analogue data (PMID 24259556)
• No long-term safety data (>2 years) for chronic supplementation
• Pharmacogenomic variants affecting normal copper metabolism (beyond ATP7A/ATP7B extremes) unstudied
• Cu/Zn ratio as clinical biomarker lacks interventional validation
• Cuproptosis implications for supplementation safety are theoretical

Bias Flags (Mode 4: First Principles)

• Most copper supplementation evidence comes from deficiency correction in specific populations — generalizability to healthy supplementation is weak
• IOM DRI (2001) is >25 years old; updated population-level data on copper adequacy would be valuable
• Cardiovascular data is observational and confounded — inflammation raises ceruloplasmin (acute phase reactant), which raises measured serum copper, which correlates with CVD. This may be reverse causation rather than copper causing CVD.
• Depression meta-analysis (PMID 41263185) finding elevated copper in MDD is almost certainly inflammatory confounding, not copper toxicity

Manipulation Flags (Mode 2: Manipulation Shield)

• Industry marketing: Minimal for standard copper supplements — commodity-priced, low-margin. MitoSynergy is the notable exception with aggressive "copper 1" marketing, premium pricing (~6× standard), and curated testimonials.
• Influencer economics: No significant influencer ecosystem. TikTok gray hair trend is organic (many small creators, no affiliate patterns). MitoSynergy has a small but dedicated promotional apparatus.
• Counter-narrative manipulation: Wilson disease toxicity concerns are legitimate but sometimes over-generalized to standard supplementation. Copper toxicity at physiologic doses (0.9-3 mg/d) in genetically normal individuals is essentially impossible.
• Cui bono summary: Copper supplements are so cheap that nobody profits significantly from promoting them. The zinc supplement industry paradoxically benefits from NOT mentioning copper (avoids the "you need both" message). Wilson disease awareness organizations appropriately raise toxicity concerns.
• Red team highlight: The most concerning angle is the depression meta-analysis finding (elevated Cu in MDD). While likely confounded by inflammation, it warrants monitoring in anyone supplementing copper who has mood disorders.

Decision Support (Mode 3: Clarity Compass)

• Health utility score: 7/10 — essential mineral with severe consequences if deficient (myeloneuropathy, anemia, connective-tissue impairment); utility is high for deficiency states and high-risk groups (high-dose zinc users, post-bariatric, chronic PPI), low incremental benefit when replete.
• Opportunity cost: Very low — $0.05-0.25/day, well-tolerated, minimal complexity
• Verdict: CONDITIONAL
• Conditions: Supplement if: (1) documented deficiency, (2) high-dose zinc user (>50 mg/d), (3) post-bariatric surgery, (4) elderly on PPIs + calcium + zinc, (5) celiac/IBD with malabsorption, or (6) chronic PPI use >2 years. For copper-replete individuals on balanced diets: no supplementation needed.

Bottom Line

Copper is a well-understood essential mineral with an excellent safety profile at physiologic doses. The evidence is ironclad for deficiency correction and negligible for supplementation enhancement in replete individuals. The primary clinical value is preventing/treating deficiency in at-risk populations — particularly the increasingly recognized post-bariatric surgery cohort and high-dose zinc users. The 2024-2026 literature adds bone health meta-analysis data, cuproptosis biology, Cu/Zn ratio as a disease biomarker, and a landmark FDA approval (Zycubo for Menkes). For biohackers: if you're taking >25 mg zinc, add 2 mg copper. If your diet includes shellfish, organ meats, nuts, and dark chocolate, you probably don't need it.

Practical Notes

Brands & Product Selection

First-line: copper gluconate from USP-verified brands (Thorne, Pure Encapsulations, Kirkland). Premium: copper bisglycinate for GI-sensitive or PPI users. Avoid copper oxide in multivitamins — check ingredients. Quality markers: specific form listed, elemental copper stated, third-party certification (USP, NSF, ConsumerLab), lot number, expiration date. Red flags: "proprietary blend," no elemental content, no testing, unrealistic claims.

Storage & Handling

Room temperature 15-25°C, dry, away from light. Shelf life: 2-3 years unopened, 12-18 months opened. Signs of degradation: darkening, clumping, unusual odor. Travel: carry-on preferred (avoid checked luggage temperature extremes).

Palatability & Compliance

Sulfate has the worst metallic taste; bisglycinate is nearly tasteless. If GI upset occurs: split dose (1 mg × 2/day), take with protein-rich non-dairy snack, or switch to bisglycinate. Capsules preferred over powder for taste. Habit stack with an existing supplement routine for consistency.

Exercise & Circadian Timing

No strong circadian variation in copper absorption (unlike iron). No acute ergogenic effect — timing relative to exercise is irrelevant. Long-term adequate copper supports connective tissue repair (lysyl oxidase) and oxidative stress management (SOD) post-exercise. Morning or evening dosing equally effective; consistency matters more than timing.

Reference Ranges (Expected Biomarker Changes)

Cost

What We Don't Know

• Whether copper supplementation provides ANY benefit in copper-replete individuals (zero RCTs)
• Optimal Cu:Zn ratio for co-supplementation (1:8 to 1:15 used clinically, never validated by RCTs)
• Whether bioavailability differences between formulations (gluconate vs bisglycinate) are clinically meaningful in humans (extrapolated from zinc data)
• Long-term safety of chronic supplementation >2 mg/d beyond 2 years
• How cuproptosis biology intersects with supplementation safety at physiologic doses
• Whether Cu/Zn ratio is a causal biomarker or just an inflammatory correlate
• Pharmacogenomic variants affecting copper metabolism in the general population (beyond Menkes/Wilson extremes)
• Whether the depression-copper association (elevated Cu in MDD) is causal or confounded by inflammation
• Optimal copper status for cancer patients (dual role: immune support vs angiogenesis)
• Whether oral copper supplementation can meaningfully affect hair pigmentation in non-deficient individuals

References

Systematic Reviews & Meta-Analyses

• PMID 39755772 — Xu et al. (2025). Copper deficiency after metabolic bariatric surgery: systematic review + meta-analysis. Obes Surg. Confirms frequently overlooked complication.
• PMID 41361655 — (2025). Meta-analysis: dietary copper intake and bone health. First systematic review on this topic.
• PMID 41263185 — Davarinejad et al. (2026). Association between serum Cu, Zn, Fe and major depressive disorder: systematic review + meta-analysis. Rev Environ Health. Elevated Cu associated with MDD.
• PMID 41677652 — (2026). Meta-analysis: Cu, ceruloplasmin, Zn, Mn in Parkinson's disease brain/fluids.
• PMID 41372683 — (2026). Zn/Cu ratio imbalance in ASD: reanalysis of 6 multinational studies.
• PMID 38690587 — (2024). Biomarkers of Zn/Cu status and heart failure: meta-analysis.
• PMID 39440586 — (2024). Micronutrients and androgenetic alopecia: systematic review.
• PMID 39390004 — (2024). Zinc, copper, selenium in vitiligo: systematic review + meta-analysis.
• PMID 35063246 — (2022). Antioxidant micronutrients in critically ill: Bayesian network meta-analysis.
• PMID 35365361 — ESPEN Micronutrient Guideline (2022). Comprehensive copper recs for clinical nutrition.
• PMID 38350290 — ESPEN Practical Short Micronutrient Guideline (2024). Condensed clinical decision support.

Landmark Reviews & Clinical Studies

• PMID 29959467 — Myint et al. (2018). Copper deficiency anemia: review. Ann Hematol. Hematologic manifestations fully reversible in 4-12 weeks.
• PMID 6410510 — Williams (1983). Copper deficiency in humans. Semin Hematol. Anemia and neutropenia as striking manifestations.
• PMID 31209935 — Altarelli et al. (2019). Copper deficiency: causes, manifestations, and treatment. Comprehensive clinical review.
• PMID 20232210 — Jaiser & Winston (2010). Copper deficiency myelopathy. J Neurol. Early treatment critical.
• PMID 40653562 — Takami & Uchino (2025). Hematological disorders caused by copper deficiency. Int J Hematol.
• PMID 38909910 — (2024). Copper deficiency myelopathy mimicking cervical spondylotic myelopathy: systematic review.
• PMID 41455456 — Huang et al. (2026). Severe polyneuropathy post-sleeve gastrectomy from copper deficiency. Nutrition. (Taiwan)
• PMID 41353140 — Moradi et al. (2025). Copper deficiency trends: OAGB vs RYGB. BMC Surg.
• PMID 41539972 — Kim et al. (2026). Prolonged zinc use for dysgeusia causing copper deficiency.
• PMID 40903224 — Ikegishi et al. (2026). Acute copper deficiency post-surgery in dialysis patient. Intern Med. (Japan)
• PMID 41591643 — Ikegishi et al. (2026). Cu deficiency mimicking MDS in dialysis. CEN Case Rep. (Japan)
• PMID 41269469 — Klevay (2025). Poor vision from copper deficiency. Review.

Mechanism & Biochemistry

• PMID 21473702 — Fukai & Ushio-Fukai (2011). SODs: role in redox signaling, vascular function, disease. Antioxid Redox Signal.
• PMID 16631971 — Cobine et al. (2006). Copper trafficking to mitochondria. BBA.
• PMID 8527222 — Vulpe & Packman (1995). Cellular copper transport. Annu Rev Nutr.
• PMID 8615367 — Linder & Hazegh-Azam (1996). Copper biochemistry and molecular biology. AJCN.
• PMID 15113938 — Prohaska & Gybina (2004). Intracellular copper transport. J Nutr.
• PMID 9587135 — Uauy et al. (1998). Essentiality of copper in humans. AJCN.
• PMID 41920999 — Usui et al. (2026). Copper deficiency impairs oligodendrocyte maturation in ASD via mitophagy/mTOR. Sci Adv. (Japan)
• PMID 41621246 — Kim et al. (2026). LRRK2 controls COX assembly via mitochondrial copper chaperones. Redox Biol. (Korea)
• PMID 41213165 — (2026). Comprehensive review: copper in human health via inherited disorder insights.
• PMID 41794315 — (2026). Copper, cuproptosis, homeostasis to pathogenesis: comprehensive review.
• PMID 41892335 — (2026). Copper homeostasis in gut health: molecular mechanisms to therapeutics.
• PMID 41650808 — (2026). Age-related redistribution of Zn/Cu within human skin.

Cardiovascular & Metabolic

• PMID 29344376 — DiNicolantonio et al. (2018). Copper deficiency as cause of ischemic heart disease. Open Heart.
• PMID 10721935 — Klevay (2000). Cardiovascular disease from copper deficiency. J Nutr.
• PMID 40716490 — Nagai et al. (2025). Trace element abnormalities in acute heart failure. J Cardiol. (Japan)
• PMID 41931731 — Selvan et al. (2026). Role of minerals in ischemic heart disease. J Physiol Pharmacol.
• PMID 41666991 — (2026). Serum Zn, Cu, Zn/Cu ratio across glycemic spectrum.
• PMID 41052303 — Li et al. (2026). Urinary copper and gestational diabetes via DNA methylation. JCEM.

Absorption & Pharmacology

• PMID 9625097 — Turnlund et al. (1998). Copper absorption by stable isotope. AJCN. 55-75% from diet.
• PMID 9587151 — Wapnir (1998). Copper absorption and bioavailability. AJCN.
• PMID 24259556 — Wedekind et al. (1992). Zinc bioavailability methodology. J Anim Sci. Analogue data for copper formulations.

Regulatory & Guidelines

• PMID 40089450 — EASL-ERN Clinical Practice Guidelines on Wilson's Disease (2025).
• IOM (2001) — DRI for Copper. RDA 900 mcg/d, UL 10 mg/d. National Academies Press.
• NIH ODS — Copper Fact Sheet for Health Professionals (2022).
• FDA NDA211241 — Zycubo (copper histidinate) approved January 2026 for Menkes disease.

Disease-Specific

• PMID 30887374 — Wegner et al. (2019). Zinc/copper in IBD. Biol Trace Elem Res.
• PMID 26293624 — Wegner et al. (2016). Serum Zn/Cu in T1DM. Biol Trace Elem Res.
• PMID 20071227 — Brewer (2010). Copper toxicity in general population. Clin Neurophysiol.
• PMID 41685405 — Yan et al. (2026). Trace elements in IBD pathogenesis. Food Funct.
• PMID 41130564 — (2026). Trace element imbalance in long-COVID.
• PMID 41759984 — (2026). Copper, cuproptosis, and male reproductive health.
• PMID 40829714 — (2025). Semen elements and male infertility: meta-analysis.

Clinical Trials & Novel Interventions

• PMID 41926471 — (2026). RCT: copper+silver nanoparticle wound dressing for diabetic foot ulcers.
• PMID 41453293 — (2025). First-in-human high-dose sodium copper chlorophyllin as immunomodulatory/antiviral. (India)
• PMID 41619405 — Simon et al. (2026). Acute effects of exercise on serum copper/zinc/selenium/iron. J Trace Elem Med Biol.