The Determination of a Human Acute No Observed Adverse Effect Level (NOAEL) for Copper: Effects of Volume and Dose. K. A. Poirier, B. H. Chen, L. Klevay, S. Strain, M. Araya, H. G. Zhu, W. Shi, L. Johnson, F. Neilsen, P. Robson, and S. Baker; Shanghai Medical University, US Department of Agriculture, Univeristy of Coleraine, and University of Chile
A human, acute NOAEL for nausea was determined in a prospective, double blind controlled study. As part of an ongoing protocol, Phase II of this study recruited 70 adult females (18-60 years of age) at each of four different international sites. The study design was a 3 x 3 factorial (volume x dose) for 100, 150, or 200 ml of drinking water for 0.4, 0.8, 1.2 mg of Cu as sulfate. Two additional doses (0 and 1.6 mg Cu) were added at the 200 ml volume to determine a dose response. Stock solutions were made fresh daily at room temperature 30 minutes prior to administration in bottled water previously supplied to each of the four test sites. Each subject was given a blind, randomly selected concentration of copper once a week over a period of 11 weeks. Following dosing, all subjects were monitored by health care personnel for 1 hour. All subjects completed a questionnaire at 0, 0.25, 1, and 24 hours post dosing that screened for positive GI effects (nausea, vomiting, abdominal pain, and diarrhea). Nausea was the most prevalent symptom reported and was generally reported within the first 15 minutes. Results were analyzed by a Generalized Linear Model (Repeated Measures) model. The four site combined data reported incidences of nausea 15 minutes post dosing of 0, 2, 7, 14, and 25% for 0, 0.4, 0.8, 1.2, and 1.6 mg Cu (or 0, 2, 4, 6, and 8 mg Cu/L) respectively. Analysis of these data indicate that for nausea alone, an acute NOAEL and LOAEL of 0.4 and 0.8 mg Cu, respectively, in natural, bottled drinking water was determined in an adult female population. There was no interactive effect between volume and dose in the factorial design. All significant increases in probability of outcome for nausea at 15 minutes occurred at copper concentrations greater than 4 mg Cu/L. The results of Phase II are in agreement with previously reported data.
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