Essentiality and toxicity in copper health risk assessment: overview, update and regulatory considerations.

Copper (Cu), an essential element required as a cofactor and/or structural component of numerous metalloenzymes, is uniquely positioned as a case study for issues associated with the essential metals health risk assessment, because of its extensive database. Essential elements pose distinct challenges when establishing regulatory guidelines because too little as well as too much intake can produce adverse health consequences and the dose-response curve is roughly U-shaped. Thus, conventional health risk assessment paradigms do not apply to essential elements; the dose-response assessment needs to define an acceptable range of oral intake (AROI) which prevents deficiency by meeting nutritional requirements while avoiding toxicity due to high intakes. The conceptual framework for this type of risk assessment includes consideration of biological processes that are unique to essential elements-homeostasis, basal and normative nutritional requirements, bioavailability, and nutrient-nutrient interactions. In this paper, the Cu database on physiology, deficiency, and excess is briefly reviewed in order to establish the range of potential health hazards associated with varying levels of intake. Issues discussed include the (1) development of suitable dose-response methodologies, including appropriate dose and response metrics, for Cu; (2) categorization of severity of response and functional significance; (3) use of endpoints of similar severity and functionality for deficiency and excess in dose-response assessment; (4) development of valid biomarkers for subclinical effects, exposures and susceptibilities. Guideline values for Cu intake have been established by nutritional and toxicologic regulatory or advisory boards. Although regulators are more concerned with the potential human toxicity arising from excessive Cu intake, the preponderance of evidence suggests that deficiency is more of a public health concern than excess.