We assessed gastrointestinal effects in 1,365 adults exposed to either < rr =" 1.9;"> 6 mg Cu/L. We conclude that exposure to Cu in drinking water results in gastrointestinal symptoms, which are modulated by Cu concentration, time, and sex.

Copper is relevant to human nutrition because it is both essential and toxic depending on the dose and duration of exposure. Ingestion of high Cu doses induces acute effects in the gastrointestinal tract, mainly in the stomach (Furukawa and Hatano 1998; Kayashima et al. 1978; Niijima et al. 1987; Wang and Borison 1951), whereas chronic effects from long-term overexposure results mainly on Cu accumulation in the liver and liver damage (Bremmer 1998). Reports of acute Cu intoxication in humans are infrequent (National Research Council 2000; Ross 1955; Spitalny et al. 1984; Wyllie 1957); the possibility that low Cu concentrations, such as those contained in drinking water, may induce acute adverse effects in humans was raised in the early 1980s and 1990s and quickly became a concern of health authorities and regulators. Most natural drinking waters have Cu concentrations not exceeding a few milligrams per liter; however, soft, acidic waters, especially when going through new Cu pipes, may deliver higher amounts of Cu (National Research Council 1980). Anecdotal and accidental random events where variable concentrations of Cu was related to acute gastrointestinal symptoms have appeared in the literature (National Research Council 2000; Ross 1955; Spitalny et al. 1984; Wyllie 1957), but the exact responses and their distribution at a given dose within a population were unknown. The current World Health Organization (WHO) provisional guideline value for drinking water of 2 mg Cu/L is based on acute gastrointestinal symptoms that are reversible in nature (WHO 1993, 2003).

Over the past decade, systematic controlled randomized studies have characterized the full response to acute Cu exposure in drinking water, defining the first adverse effect rather than toxic effects (Araya et al. 2001; Olivares et al. 2001; Pizarro et al. 1999). In these studies, clinical assays using controlled exposure were performed including asymptomatic participants 18-60 years of age, balanced by sex, who were exposed to a single bolus of different waters containing Cu sulfate in concentrations ranging from 0.01 to 12 mg Cu/L. The first and most frequent symptom reported was nausea, which was transient, appearing mainly within 15 min after ingestion (Araya et al. 2001; Gotteland et al. 2001; Olivares et al. 2001; Pizarro et al. 1999). The no observed effect level (NOEL) was 2 mg Cu/L, and the lowest observed adverse effect level (LOAEL) for nausea was 4 mg Cu/L (Olivares et al. 2001). At testing concentrations of up to 12 mg Cu/L, the authors reported that nearly one-third of the subjects remained asymptomatic. Vomiting was observed in 11.5% of the study subjects and was first reported at 6 mg/L, showing a 2-fold increase when the Cu concentration reached 10-12 mg Cu/L. Diarrhea and abdominal cramps were rare within the range of concentrations studied (Araya et al. 2001; Gotteland et al. 2001; Olivares et al. 2001; Pizarro et al. 1999). Using these dose-response curves and the 95% confidence intervals (CI), the Cu concentration at which 5% of the population would experience nausea was 2.0 mg Cu/L for the crude initial response and 4.2 mg Cu/L for the nausea response confirmed by repeat testing (Olivares et al. 2001). Another study emphasizing the interindividual variability of responses across countries included volunteers from the United States, Northern Ireland, and Chile. Using the pooled data obtained in the three countries and statistical significance to define a level, the NOEL and LOAEL for water were determined to be 4 and 6 mg Cu/L (Araya et al. 2001).

Because an epidemiologic study using natural exposure to Cu in water would be difficult to carry out, we decided to conduct a controlled exposure study in a community whose members maintained living conditions as close to real life as possible.