While copper is an essential nutrient for humans, animals, and plants, it can pose risks to human health with elevated exposure. In addition to diet and supplements, a prevalent source of copper exposure in the US is through leaching of copper from plumbing into tap water. As of 2016, 78% of newly installed utility lines used copper (CDA 2016), and it is estimated that 35–40% of single-family homes newly constructed in 2019 will have copper piping (Personal communication with CDA). Copper exposure through drinking water has been regulated in the United States since 1991 (56 FR 26460-26564), when the US Environmental Protection Agency (EPA) set a maximum contaminant level goal (MCLG) and drinking water action level for copper at 1.3 mg Cu/L. EPA based the MCLG on acute gastrointestinal effects observed in nurses who consumed cocktails contaminated with copper (Wyllie 1957) (estimated minimal dose of 2.65 mg Cu/L, divided by an uncertainty factor of 2) (Donohue 1997). Although a broader review of the scientific basis for this drinking water level was conducted for EPA in 2000 (NRC 2000), which concurred with this level at the time, EPA has not since reevaluated the MCLG or formally developed an oral reference dose (RfD) to support risk assessments of environmental copper exposure. An update of the literature and an assessment of an RfD would thus be timely.
Copper has been reviewed by numerous health authorities. EPA’s Integrated Risk Information System (IRIS) evaluated copper in 1987; however, neither an oral RfD nor an inhalation reference concentration were derived (IRIS 2017), likely due to the lack of information at the time (US EPA 1988a). In 2000, EPA commissioned the National Research Council (NRC) to review the 1.3 mg Cu/L EPA drinking water action level in light of more recent experimental data on acute gastrointestinal effects in humans at that time (NRC 2000). A controlled human study reported gastrointestinal symptoms at copper levels in drinking water of ~3 mg Cu/L with no effects at 2 mg Cu/L (Pizarro et al. 1999), which was supported by unpublished data from another study sponsored by the International Copper Association. Nevertheless, NRC (2000) did not recommend increasing the MCLG because of concern for susceptible individuals with copper homeostasis disorders. The NRC reviewed both food and water ingestion studies and concluded that 1.3 mg Cu/L was protective for both gastrointestinal effects of acute exposures to elevated copper in water as well as for the rare occurrences of liver toxicosis in genetically susceptible infants or children consuming milk with elevated copper levels (NRC 2000). Subsequently, the European Chemicals Agency reviewed and endorsed a voluntary risk assessment written by the European Copper Institute (ECI) on copper and copper compounds that determined that environmentally relevant concentrations of copper were of no concern (ECI 2008).
In absence of an oral RfD, EPA and some states (e.g., New Jersey) have converted the 1.3 mg Cu/L EPA action level for drinking water to an RfD of 0.04 mg Cu/kg/day assuming 2 L/day of water consumption and a 70-kg body weight (US EPA 2017). Other state, national, and international health authorities have also developed various allowable doses for copper risk assessment, allowable dietary intake, or limits for copper in drinking water. The World Health Organization (WHO) reported that 104 countries have a regulation or guideline for copper in drinking water, with a median value of 1.5 mg/L and a range of 0.05–3 mg/L (WHO 2018).
For essential mineral elements such as copper, WHO recognized the complexity of assessing limits for copper intake and defined an acceptable range of oral intake as the trough in a U-shaped curve that balances deficiency of low exposure with toxicity from excess exposure (WHO 2002). Although an oral RfD is not intended to provide essential intakes for good health, an RfD in the range of deficiency is lower than necessary for protection against toxicity from excess. Derivation of an oral RfD for copper thus needs to consider toxicity data in animals, human experimental studies, and epidemiological studies, along with the mechanistic effects of copper as an essential element in biological functions, tolerance over a wide range of doses from internal regulation of copper levels, and toxicity that results from excess internal copper, especially for some uncommon genetically susceptible groups.
Though increasing copper exposure in the US population is not a concern, a better understanding of the levels of essentiality and toxicity is needed to support the scientific basis of health-protective regulations for this element. The objectives of this review are to summarize the current knowledge on copper toxicity, assess dose-response endpoints, and provide useful information for health professionals, regulatory agencies, and policy makers for assessing the health risks of copper and determining whether current research warrants reevaluation of copper criteria for risk assessment and risk management of environmental exposures.
