An Exposure-Response Curve for Copper Excess and Deficiency

Abstract

There is a need to define exposure-response curves for both Cu excess and deficiency to assist in determining the acceptable range of oral intake. A comprehensive database has been developed where different health outcomes from elevated and deficient Cu intakes were assigned ordinal severity scores to create common measures of response. A generalized linear model for ordinal data was used to estimate the probability of response associated with dose, duration and severity. The model can account for differences in animal species, the exposure medium (drinking water and feed), age, sex, and solubility. Using this model, an optimal intake level of 2.6 mg Cu/d was determined. This value is higher than the current U.S. recommended dietary intake (RDI; 0.9 mg/d) that protects against toxicity from Cu deficiency. It is also lower than the current tolerable upper intake level (UL; 10 mg/d) that protects against toxicity from Cu excess. Compared to traditional risk assessment approaches, categorical regression can provide risk managers with more information, including a range of intake levels associated with different levels of severity and probability of response. To weigh the relative harms of deficiency and excess, it is important that the results be interpreted along with the available information on the nature of the responses that were assigned to each severity score.

The views and conclusions in this article are those of the authors and do not represent policies of or endorsement by U.S. EPA or other agencies with which the authors are affiliated. Laura Plunkett was working as a consultant for the International Copper Association. Peter Aggett was involved in the preparation of one of the studies in the Cu database (Harvey et al., 2003).

Notes

¹A “U-shaped” exposure-response curve results when the curves for Cu deficiency and excess are plotted on a continuum from very low doses of Cu to high doses of copper (x axis) and the likelihood of adverse events (y axis) increases with both very low doses of Cu and very high doses of Cu.