Confirmation of an acute no-observed-adverse-effect and low-observed-adverse-effect level for copper in bottled drinking water in a multi-site international study.

In a double blind, 3x3 factorial (volumexdose) study, 70 adult females (18-60 years of age) at four different international sites (total pooled n=269) were given 100, 150, or 200ml of bottled drinking water with 0.4, 0.8, or 1.2mg 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 1h 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 15min (water volume, p<0.032; copper dose, p<0.0001; and water volumexcopper interaction, p<0.97). As volume increased, the effect of Cu-induced nausea decreased; as Cu dose increased, the incidence of nausea increased. At 200ml, a significant increase in reported incidence of nausea at 0.25h occurred at 1.2 mg Cu (6mg Cu/L), indicating a NOAEL of 0.8mg Cu (4mg 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.