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.

Determination of an acute no-observed-adverse-effect level (NOAEL) for copper in water.

A prospective, double-blind controlled study was designed to determine the acute no-observed-adverse-effect level (NOAEL) of nausea in an apparently healthy population of 179 individuals who drank copper-containing water as the sulfate salt. Subjects were recruited at three different international sites and given a blind, randomly selected dose (0, 2, 4, 6, or 8 mg Cu/L) in a bolus of 200 ml (final total copper dose was equivalent to 0, 0.4, 0.8, 1.2, and 1.6 mg) once weekly over a consecutive 5-week period. Gastrointestinal (GI) symptoms of nausea, abdominal pain, vomiting, or diarrhea were screened for a period of up to 24 h. Nausea was the most frequently reported effect and was reported within the first 15 min of ingestion. For the combined trisite population (n=179), 8, 9, 14, 25, and 44 subjects responded positively to one or more GI symptoms at 0, 2, 4, 6, and 8 mg Cu/L, respectively. Analysis of the data demonstrated a clear dose response to the combined positive GI effects and to nausea alone. Statistically significant greater reporting of effects occurred at 6 and 8 mg Cu/L. Therefore, an acute NOAEL and lowest-observed-adverse-effect level of 4 and 6 mg Cu/L (0.8 and 1.2 mg Cu), respectively, were determined in drinking water for a combined international human population.