Lines of Evidence	Influence on conclusion
Line of Evidence 1 ‐ Homeostatic mechanisms tightly regulate copper absorption, distribution, sequestration and excretion, preventing the appearance of copper in chemical forms that are able to promote oxidative damage to cellular components.	↑↑↑
Line of Evidence 2 – When copper balance is positive (i.e. copper retention), evidence suggests that additional copper is sequestered in the liver and MT acts as a sink for hepatic copper.	↑↑↑
Line of Evidence 3 – Copper is increasing in the liver when physiological needs are met, when homeostasis is overwhelmed, such as when exposure is very high, or when excretion is compromised by genetic disease (as in WD) or cholestasis.	↑↑↑
Line of Evidence 4 – Supporting evidence for hepatic copper retention is obtained from 90‐day studies in rats.	↑↑
Line of Evidence 5 – Liver copper levels increase in farm animals consuming feed with high copper levels.	↑↑
Line of Evidence 6 – There is absence of direct measurements of hepatic copper in the general population.	?
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 supports the premise that copper is sequestered in the liver at levels of exposure above those that meet physiological functions.	Extremely likely (95–99% probability) to almost certain (99–100% probability)