In a double blind, 3 x 3 factorial (volume x dose) study, 70 adult females (18-60 years of age) at four different international sites (total pooled n = 269) were given 100, 150, or 200 ml of bottled drinking water with 0.4, 0.8, or 1.2 mg of copper (Cu) as the sulfate salt once each week. Two additional doses (0 and 1.6mg Cu) were added at the 200ml volume to determine a dose-response relationship and corroborate previously reported results. All subjects completed a questionnaire at 0, 0.25, and I h post-dosing that screened for positive gastrointestinal (GI) effects (nausea, vomiting, abdominal pain, and diarrhea). Nausea was the most prevalent symptom reported and was generally reported within the first 15 min (water volume, p < 0.032; copper dose, p < 0.0001; and water volume x copper interaction, p < 0.97). As volume increased, the effect of Cu-induced nausea decreased; as Cu dose increased, the incidence of nausea increased. At 200 ml, a significant increase in reported incidence of nausea at 0.25 h occurred at 1.2 mg Cu (6 mg Cu/L), indicating a NOAEL of 0.8 mg Cu (4 mg Cu/L) for adult females. These data confirm a previously determined human acute NOAEL for Cu added to distilled water, and provide additional, controlled human data for determining safe concentrations of Cu in drinking water. (C) 2003 Elsevier Inc. All rights reserved.