Urban JD, Thompson CM, Plunkett LM, Perry CS, Haws LC. 2015. A state of the science copper reference dose for soil remediation. Presented at the Society of Toxicology’s 54th Annual Meeting, March 22-26, San Diego, CA.
Copper (Cu) is an essential micronutrient that has a U-shaped dose-response curve, with both chronic deficiency and excess resulting in adverse effects. Although acute excess intake can produce transient GI symptoms, chronic intake of excess Cu leads to Cu accumulation in the liver, and the resulting oxidative stress can lead to cirrhosis, followed by kidney and CNS damage. The dose-response relationship for Cu, therefore, presents a challenge for risk assessment. The current USEPA reference dose (RfD) (0.04 mg Cu/kg/d) is based on an abstract describing an acute poisoning event at a 1950s cocktail party. More recently, a review by an expert panel indicated steep dose-response curves and a narrow margin of safety between Cu essentiality and excess; this effort, however, was not intended to identify individual points of departure that could be used to derive copper RfD values. Given the availability of more recent data that is both more robust and relevant, an effort was undertaken to develop a chronic RfD that reflects the current state of the science and is appropriate for deriving soil remediation standards. Since such standards assume risks and hazards based on chronic exposures, we focused our review of the Cu toxicology literature on repeated exposure scenarios and measures of chronic toxicity where possible. Four critical Cu toxicology studies were identified (two human, one monkey, one rat), and points of departure were derived. Benchmark dose modeling was performed when possible; otherwise NOAEL and LOAEL values were used. Candidate RfDs based on typical risk assessment practices for human and animal studies led to similar values, ranging from 0.1 to 0.35 mg/kg/d. Based on the overall weight of the evidence from the above studies, an RfD of 0.1 mg/kg/d is proposed based on evidence that 0.13 mg/kg/d is safe to adults and 0.29 mg/kg/d has been reported to be safe for infants.