THE U.S. Environmental Protection Agency (EPA) is required under the Safe Drinking Water Act (SDWA) to establish the concentrations of contaminants permitted in public drinking-water supplies. Enforceable standards are to be set at concentrations that have no observable adverse health effects with adequate margins of safety and are attainable with the use of the best available technology. The maximum contaminant level (MCL) is the term used for enforceable standards. The maximum contaminant level goal (MCLG) is based on available scientific data. It is not a regulatory requirement, and, in principle, it might not be attainable with current technology. According to the SDWA, the MCL should be set as close to the MCLG as is feasible with available technology. The MCLG for copper will be used by EPA as a basis for establishing the MCL.
Copper is a naturally occurring element that is present in drinking water. Stagnation of water in pipes and plumbing fixtures containing copper and copper alloys in distribution systems and household plumbing allows leaching and increases water copper levels. Characteristics of the water, including increased acidity, increased temperature, and reduced hardness, can increase the leaching of copper into the water.
Acute ingestion of excess copper in drinking water is associated with adverse health effects, including acute gastrointestinal disturbances, and chronic ingestion of copper can lead to liver toxicity in sensitive populations. The current EPA MCLG of 1.3 milligrams per liter (mg/L) for copper in drinking water is based on the need to protect against adverse gastrointestinal effects. Some states and municipalities have difficulty maintaining copper levels below the MCLG primarily because of the characteristics
of their water. Questions have been raised about the validity of the science on which the MCLG is based and whether that level is appropriate. Some believe that the level might be unnecessarily low, and others believe that some individuals might have adverse health effects with copper levels at or below the current MCLG.
THE CHARGE TO THE COMMITTEE
At the direction of Congress, EPA asked the National Research Council (NRC) to review independently the scientific and technical basis for EPA's MCLG of 1.3 mg/L for copper in drinking water. For the review, the NRC convened the Committee on Copper in Drinking Water, whose members have expertise in the fields of toxicology, epidemiology, pathology, pharmacology, genetics, physiology, medicine, public health, exposure assessment, nutrition, chemistry, biostatistics, and risk assessment. The committee reviewed available toxicological, epidemiological, and exposure data (from food and water) and determined the appropriateness of the critical study used for deriving the MCLG, end points of toxicity, and uncertainty factors used by EPA in the derivation of the MCLG for copper. The committee was also asked to identify data gaps and make recommendations for future research. The committee was not asked to address risk-management issues.
THE COMMITTEE'S APPROACH TO ITS CHARGE
The committee evaluated data relating to key elements of the risk-assessment process that led to the current MCLG. The key elements are hazard identification, dose response, exposure assessment, and risk characterization. The current MCLG is based on gastrointestinal effects following acute exposure to copper. However, effects on the liver have been observed with chronic exposure in sensitive populations. Therefore, in this report, the committee reviewed information on the health effects of copper exposure in humans following both acute and chronic oral exposure. The committee also evaluated data on the mechanisms of action of copper toxicity, the health effects associated with copper deficiencies, and factors affecting the bioavailability of copper—all data that could affect the risk assessment. The toxicity of copper was used as the basis for evaluating the safety of copper concentrations in drinking water, but the essential need for copper as a micronutrient (i.e., the dietary essentiality of copper) was taken into account when considering uncertainty factors.
To provide background information on relevant issues in copper toxicity,
various government representatives and trade organizations gave presentations to the committee. Those presentations included representatives of EPA, who sponsored the report, the office of Senator J. Robert Kerrey (Nebraska), and the International Copper Association. The committee also heard from scientists with relevant expertise in copper toxicity and from the Institute of Medicine's Food and Nutrition Board regarding the essentiality of copper.
The committee recognized that exposure to copper can occur from multiple sources; however, emphasis was placed on the human health effects associated with exposure through ingestion of drinking water. The committee did consider the contribution of copper in food. Exposure via inhalation or dermal routes (e.g., shower or bath) were not addressed.
THE COMMITTEE'S EVALUATION
Health Effects of Excess Copper
The primary health effects following acute exposure to copper are gastrointestinal disturbances, including nausea and vomiting. Direct irritation of the stomach by copper ions appears to underlie the acute toxic response. Although a number of cases of copper toxicity in humans have been reported in the literature, few are suitable for identifying minimal concentrations at which effects are seen. Those studies provide qualitative information on gastrointestinal end points but are not suitable for establishing an MCLG. Currently, the MCLG is based on one such case report. A recently published controlled study in humans, however, was designed to determine the copper concentration in water at which gastrointestinal disturbances occur. That study indicates that gastrointestinal symptoms arise from drinking water with copper at approximately 3 mg/L. Information provided to the committee by the International Copper Association on a controlled study of gastrointestinal effects of copper appears consistent with the data in the published study.
The main concern regarding chronic exposure to excess copper is liver toxicity, especially in sensitive populations. A number of chronic cases of liver toxicity have been reported. A model for those chronic effects might be derived from patients with Wilson disease, which causes abnormal copper regulatory mechanisms that result in accumulation of excess copper. The liver and brain are targets of copper toxicity in patients with Wilson disease. Although the mechanisms by which chronic copper exposure causes damage are not fully understood, evidence suggests that as copper regulatory mechanisms are surpassed, large amounts of copper are released into the bloodstream, and oxidative damage results. Excess dietary
copper has not been associated with adverse effects on reproduction and development in humans. The only reported association between dietary copper and cancer is in patients with Wilson disease, in which the association appears to be secondary to liver toxicity.
In general, animal models provide qualitative insight into the toxicology of copper, but they are of limited value for establishing dose-response relationships in humans. However, animal strains that are sensitive to copper because of genetic alterations provide valuable information on the effects and mechanisms of copper-induced toxicity in genetically sensitive populations.
The committee recommends that studies be conducted to establish the frequency and characteristics of gene defects in humans with Wilson disease. Characterization of the genetic basis of infant and childhood copper toxicosis should also be undertaken. Genetic animal models should be used to investigate the physiological role of copper and as models of genetically sensitive human populations. Such research should be designed to determine the association between liver toxicity and copper in sensitive populations, including Wilson-disease individuals, heterozygotes for the Wilson-disease gene, and other populations (e.g., Tyrolean infantile cirrhosis (TIC), Indian copper toxicosis (ICT), and idiopathic copper cirrhosis (ICC)) (see Sensitive Populations section below). Epidemiological studies of populations who have been chronically exposed to elevated copper should also be carried out to determine the nature and frequency of chronic effects, especially in sensitive populations.
Physiological Role of Copper
Copper is an essential micronutrient that has multiple metabolic functions. Severe copper deficiencies are associated with cardiac, bone, immune, and central-nervous-system problems. Ingested copper is readily absorbed from the intestines and transported to the liver. Specific transport molecules for copper control its movement from the liver to other tissues, and enzymes regulate its excretion into the bile. A number of factors can affect the bioavailability of copper. The percentage of copper that is absorbed changes with the amount of copper needed by the body, with age, and with dietary factors. Dietary factors include the amount of amino acids in the diet, competing metal ions, and the amount of plant versus animal protein that an individual ingests. The mechanisms by which copper is absorbed and distributed to the tissues in the body and by which copper concentrations are regulated are not fully understood.
The committee recommends that further research be carried out to determine the mechanisms that underlie the absorption, distribution, and regulation of copper in the body. Continued research on the role of copper in the body is warranted, with an emphasis on the consequences of both copper deficiency and copper toxicity. Such research could provide mechanistic data and information on the interactions between copper and other factors that could be used to refine risk assessments.
The committee concludes that there are disorders in copper homeostasis in some individuals that are important to consider in the regulation of copper in drinking water. Those include Wilson disease, heterozygote carriers of the gene for Wilson disease, Tyrolean infantile cirrhosis (TIC), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT).
Wilson disease is a genetic disorder that has a recessive inheritance pattern—that is, two mutated copies of the gene must be present to manifest the full disease. The frequency of Wilson disease in the United States is relatively low (1 in 40,000).
Individuals who have only one mutated copy of the gene for Wilson disease (i.e., heterozygote carriers) also have abnormal copper regulation and can have a build-up of copper in the body. It can be calculated from the frequency of the disease that 1% of the general population is heterozygotic for a Wilson gene defect. Unlike Wilson-disease patients, heterozygous individuals are largely unrecognized in the population. The committee concludes that those individuals, perhaps identified by examining families with a medical history of Wilson disease, should be considered in establishing copper drinking-water standards.
TIC, ICC and ICT are all syndromes in which infants or young children are afflicted with liver disease. All three syndromes appear to have a genetic component. There is evidence in cases of TIC and ICC and in some cases of ICT that an increased ingestion of copper precipitated the disease. Those cases represent other groups who should be considered when regulating copper in drinking water.
Populations that are sensitive to excess copper in drinking water should be investigated, especially those with genetic abnormalities that might increase the risk of developing copper toxicity. Novel mechanisms that might be important in copper toxicity and imbalance should be examined.
In characterizing the risks of copper, the committee noted that adverse health effects are associated with both copper deficiency and copper excess. The committee considered the dietary essentiality of copper when discussing the uncertainty factors that are appropriate in setting an MCLG. Because the MCLG is intended to be protective against copper toxicity, the committee concluded that the MCLG for drinking water should be based on toxicity, not copper deficiency.
The main toxic end points of concern to the committee were nausea and vomiting following acute exposure to copper in drinking water, and liver effects in sensitive populations following chronic exposure. For acute effects, the committee concluded that experimental studies in humans are the most appropriate for deriving the MCLG. Although the precise concentrations at which acute effects occur are difficult to determine, the one relevant published study showed that gastrointestinal effects occurred following acute exposure at and above 3 mg/L. In establishing the MCLG for gastrointestinal effects from acute exposure, the fact that the effects are mild and not life-threatening, and that the data are from humans are important considerations.
In sensitive populations, liver toxicity can occur following chronic exposure to excess copper. The available data are plagued by imprecise exposure measurements, but there is some indication that sensitive infants might be at risk for liver toxicity at copper concentrations of approximately 3 mg/L of drinking water.
Survey data indicate that numerous water systems have first-draw-water copper concentrations in selected homes above the current MCLG. Some copper concentrations are above 3 mg/L, indicating the potential for copper toxicity. Because of the low probability that a sensitive individual would consume a sufficient volume of first-draw water at a high copper concentration, toxicity is unlikely to occur often. For toxicity to occur, first, a sensitive individual must be in a household with high concentrations of copper in water, and second, that individual must be the one who consumes the first-draw water.
The committee recommends that the MCLG for copper in drinking water be based on the toxic effects of copper, rather than on copper deficiency. Issues that should be considered in establishing adjustment and uncertainty factors for acute effects are that copper is an essential micronutrient, that the GI effects are not severe or life-threatening, that the effect level is based on human studies and case reports, and that the effect level
appears to be at the lower part of the dose-response curve, where the majority of the population is nonresponsive.
Given the potential risk for liver toxicity in individuals with polymorphisms in genes involved in copper homeostasis, the committee recommends that the MCLG for copper not be increased at this time.
Additional information on total copper doses received from drinking water is needed before systemic chronic toxicity can be evaluated in susceptible populations. Better quantification of the frequency and characterization of copper-sensitive populations should be undertaken. When the above information on sensitive populations is obtained, the MCLG for copper should be re-evaluated.