Lines of Evidence	Influence on conclusion
Line of Evidence 1 ‐ Hepatic sequestration is part of homeostasis and functions as a high capacity protective mechanism against the adverse effects of this transition metal in the general population	↓↓↓
Line of Evidence 2 – Hepatic sequestration may lead to redistribution of copper complexes into subcellular pools able to promote oxidative damage	↑
Line of Evidence 3 ‐ Evidence of hepatic toxicity from locally sequestered copper is limited and is based on models indicating that protein‐bound copper may still participate in redox activity	↑
Line of Evidence 4 ‐ Copper is sequestered in the liver of WD patients for many years with no overt toxicity (long duration), at significantly higher hepatic concentrations than those expected from estimated daily exposure in non‐WD individuals	↓↓
Line of Evidence 5 ‐ Absence of evidence of hepatic toxicity in human intervention studies of short duration at relatively low copper doses and in observational studies at relatively low copper levels in drinking water, where copper can be assumed to be effectively sequestered as of LoE 1 and 4	↓↓↓
Conclusion – based on a process of weighing the influence of the different lines of evidence, their consistency and semi‐formal expert judgement, the overall evidence does not support the premise that copper effectively sequestered in the liver causes hepatotoxicity.	Extremely unlikely (1–5% probability)