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United States Department of Agriculture

Agricultural Research Service

Title: Determination and Confirmation of An Acute No-Observed-Adverse Effect Level (Noael)for Copper in Drinking Water

Authors
item Araya, Magdalena - UNIV OF CHILE
item Klevay, Leslie
item Strain, J - UNIV OF ULSTER
item Robson, Paula - UNIV OF ULSTER
item Nielsen, Forrest
item Olivares, Manual - UNIV OF CHILE
item Pizarro, Fernando - UNIV OF CHILE
item Johnson, Luann - UNIV OF NORTH DAKOTA
item Poirier, K - UNIV OF CHILE
item Chen, Binheng - FUDAN UNIVERSITY
item Shi, Wei - FUDAN UNIVERSITY
item Zhu, Huigang - FUDAN UNIVERSITY
item Haber, Lynne - TOXIC EXCELL RISK ASSESS

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: September 30, 2003
Publication Date: October 13, 2003
Citation: Araya, M., Klevay, L.M., Strain, J.J., Robson, P., Nielsen, F.H., Olivares, M., Pizarro, F., Johnson, L., Poirier, K.A., Chen, B., Shi, W., Zhu, H., Haber, L.T. 2003. Determination and confirmation of an acute no-observed-adverse-effect level (NOAEL)for copper in drinking water. [Abstract]. Web-based European Knowledge Network on Water (WEKNOW) Drinking Water Conference, October 13-14, 2003, Kuopio, Finland.

Technical Abstract: Since the mid 1950s, there has been concern that the amounts of copper found in drinking water could result in adverse gastrointestinal (GI) effects in free-living humans. Indeed, anecdotal reports have demonstrated that consuming beverages or water contaminated with variable copper concentrations can result in epigastric pain, nausea, vomiting and diarrhea. However, the data from several of the anecdotal reports are not repeatable, and interpretation of the data is complicated by unknown factors such as variations in inter and intra-individual responses to copper, the type of copper salts in the waters/beverages consumed, and potential adaptation to prolonged higher exposures of copper. Despite these limitations, such data have been used to inform the development of guidelines and legislation concerning levels of copper in drinking water, such as the maximum contaminant level goal of 1.3mg Cu/L set by the US Environmental Protection Agency (6), and the drinking water guideline of 2mg Cu/L suggested by the World Health Organization. Owing to the paucity of well controlled, randomized trials designed specifically to define the tolerable levels of copper in drinking water, the primary goal of the research described in this summary document was to determine the threshold for acute GI effects associated with drinking water containing varying copper concentrations. The work was undertaken in two phases. In phase I, the aim was to determine the acute NOAEL (No-Observed-Adverse-Effect-Level) for copper (as CuSO**4.5H**2O dissolved in distilled deionized water) in an international, culturally diverse population recruited from three sites (Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile; Grand Forks Human Nutrition Research Center, ND, US; and the Northern Ireland Centre for Food and Health, University of Ulster, Coleraine, Northern Ireland). In phase II, the aims were (i) to attempt to confirm the NOAEL for copper (as CuSO**4.5H**2O dissolved in a commercially available bottled mineral water) found in phase I, (ii) to increase cultural and geographic diversity by adding a new study site (Fudan University, Shanghai, China), and (iii) to determine the effects of copper dose and water volume as interacting variables. In order to minimize between-centre variation, all protocols, questionnaires, data sheets, and operational definitions of the outcome variables were standardized over all sites. In both phases, study progress was monitored by Toxicology Excellence for Risk Assessment (TERA), a non-profit risk assessment research organization. Ethical approval was provided by each site's Institutional Review Board or Ethics Committee, and subjects recruited for each phase at each site provided informed written consent prior to participation. At each of the three sites, 60 adults were recruited, with approximately equal numbers of men and women. 179 subjects completed the study. A single lot of CuSO**4.5H**2) (USP) pro analysis grade (Fisher Scientific, NJ, USA) was distributed to the three study sites. At each site, four test solutions (2, 4, 6 and 8mg/L of copper) were prepared daily by dissolving CuSO**4.5H**2O in distilled deionised water. The bolus of water administered to each subject on each study occasion was 200 ml, providing a dose of 0.4, 0.8, 1.2 and 1.6mg of elemental copper per dose, respectively. A 200 ml volume containing distilled deionised water only was used as the control. Subjects fasted overnight and came to each test facility on one morning a week for five successive weeks. On arrival, individuals were asked to complete a questionnaire containing a list of symptoms, indicating whether these were present or absent. The list of symptoms included the primary GI outcome variables (nausea, abdominal pain, vomiting, and diarrhea), as well as several distractor symptoms (backache, sweating, palpitations, heartburn, headache, feeling of anxiety, dizziness and salivation). If the subject was asymptomatic, he or she was asked to drink one 200 ml solution containing 0, 2, 4, 6 or 8mgCu/L. Doses were assigned to each subject in a random order, and were blinded both to the experimental subject and the person administering the solution. The symptoms questionnaire was completed again by subjects at 15 minutes, 1 hr and 24 hr after administration of each bolus. The primary outcome was the occurrence of one or more GI outcome symptoms (nausea, vomiting, diarrhea or abdominal pain) after consuming a given test solution. Data were modeled using logistic regression in SAS/Stat (SAS Institute Inc, Cary NC, USA) and dose-response estimated and odds ratios were generated from the final model. Nausea was the most frequently reported GI effect, and was reported within 15 minutes of ingestion of the 200 ml test bolus. For the combined tri-site population, 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 significantly greater reporting of effects occurred at 6 and 8mgCu/L. Therefore, an acute NOAEL of 4mg Cu/L was determined in drinking water for a combined international human population. At each of the four study sites, 70 adult females were recruited by local advertisement. Two-hundred sixty-nine women completed the study. A single lot of CuSO**4.5H**2O (USP) pro analysis grade (Fisher Scientific, NJ, USA) was distributed to the four study sites. In addition, a single lot of bottled, natural spring water was obtained from a water bottling company (Naya Inc, Quebec, Canada) and was distributed in sufficient quantity to each site. Copper contamination was not detected in the bottled water at a minimum detection level of 0.002mg/L. A stock solution of 80mg Cu/L (CuSO**4.5H**2O in the bottled water) was prepared daily at each site, and was serially diluted until the desired concentrations of copper were achieved. The study protocol followed a 3x3 two-way (volume x dose) factorial design, with doses of 0.4, 0.8 and 1.2mg Cu, and volumes of 100, 150 and 200ml bottled drinking water. An additional two doses (0 and 1.6mg Cu) were added at the 200ml volume. Thus, the final copper concentrations in the 100ml water volume were 4, 8 and 12mg Cu/L; in the 150 ml water volume were 2.6, 5.3 and 8mg Cu/L; and in the 200ml water volume were 0, 2, 4, 6 and 8 mg Cu/L. At each site, subjects fasted overnight and came to the test facility on 11 different occasions. On arrival, individuals were asked to complete a questionnaire containing a list of symptoms, indicating whether these were present or absent. The list of symptoms was the same as that described for phase I. If the subject was asymptomatic, he or she was asked to drink one of the test solutions described above. Doses were assigned to each subject in a random order, and were blinded both to the experimental subject and the person administering the solution. The signs and symptoms questionnaire was completed again by subjects at 15 minutes and 1 hour after administration of each test bolus. The primary outcomes were (i) the occurrence of one or more GI outcome symptoms (nausea, vomiting, diarrhea or abdominal pain) and (ii) the occurrence of nausea alone after consuming a given test solution. Data were modeled using logistic regression in SAS/Stat (SAS Institute Inc, Cary, NC, USA), and dose-response estimates and odds ratios were generated from the final model. Nausea was the most frequently reported GI effect, and was reported within 15 minutes of ingestion of the test bolus. As the volume of the test bolus increased, the effect of copper induced nausea decreased, and as copper dose increased, the incidence of nausea increased. At the 200ml volume, there was a statistically significant increase in the reported incidence of nausea at 1.2mg Cu (6mg Cu/L), indicating a

Last Modified: 12/18/2014
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