Determining soil remedial action criteria for acute effects: The challenge of copper
Highlights
► We used Monte Carlo methods to develop a cleanup level for copper in soil. ► We developed a copper cleanup level to minimize gastrointestinal symptom episodes. ► Soil near copper smelters may cause gastrointestinal effects in children.
Introduction
Copper, which is an essential nutrient, is unusual in that it causes acute toxicity at lower exposure levels than chronic toxicity. Acute effects of copper ingestion consist of gastrointestinal (GI) symptoms, primarily nausea, as well as abdominal pain and vomiting. The GI effects of copper generally occur immediately following exposure, and are readily reversible once exposure ceases (Araya et al., 2003a). As discussed by Olivares et al. (2001), copper interacts with mucosal cells in the stomach and triggers a vagal response. At levels of copper intake that cause GI symptoms, there is no evidence of either acute or chronic systemic copper toxicity, such as effects on the liver or the kidney. This is in part because the acute toxic response to copper occurs prior to its absorption and distribution throughout the body.
The paradox of acute effects occurring in the absence of systemic toxicity relates to copper’s role as an essential nutrient. Copper is an important component of key enzymes involved in a wide range of physiological processes, including cellular energy production, anti-oxidant defense, production and metabolism of catecholamines (e.g., epinephrine, norepinephrine, dopamine), development of connective tissue, and inactivation of histamines (IOM, 2001). Therefore, adverse health outcomes can result not only from the toxic effects of copper, but also from deficient copper intake. As with other essential nutrients, physiological mechanisms control levels of copper in the body to maintain homeostasis without causing adverse health outcomes due to either deficient or excess copper intake. If excess copper is ingested, such as in drinking water or soil, absorption is decreased, and excretion from the body is increased (Lopez de Romaña et al., 2011). Hence, when excess copper is ingested, acute GI effects can occur in the absence of systemic toxicity.
Observational studies/case reports involving repeated exposures to relatively high levels of copper in drinking water provide evidence regarding the reversibility and lack of systemic toxicity following acute exposure to copper. Spitalny et al. (1984) reported on three of four family members who experienced recurrent acute GI symptoms after drinking juice, coffee, or water in the morning. These symptoms subsided when the family members stopped consuming copper-containing water, and there were no other reports of permanent, systemic health effects. Knobeloch et al. (1994) similarly reported five case studies in which consumption of copper-containing drinking water was suspected of causing GI effects such as vomiting, diarrhea, and abdominal pain. These symptoms subsided when consumption of copper-containing water was discontinued, with no reports of permanent systemic effects, even following relatively long term exposures to copper in drinking water (up to 5 years).
Controlled exposure studies similarly demonstrate the reversibility and lack of systemic toxicity of copper. An acute toxicity study with single bolus dosing by Araya et al. (2003a) evaluated the incidence of GI symptoms in individuals consuming copper in drinking water following an overnight fast, and found that the majority of GI symptoms occurred within the first 15 min following ingestion of copper in drinking water, and subsided within an hour. Although this study by Araya et al. (2003a) did not evaluate systemic toxicity, another study by Araya et al. (2003b) evaluated both acute and chronic toxicity of copper among individuals ingesting defined concentrations of copper in their drinking water throughout the day for a period of 2 months. In this study, the frequency of study participants reporting GI symptoms increased with copper concentrations, but there was no accompanying change in indicators of copper status or liver function, as measured by blood levels of copper, ceruloplasmin, liver transaminase enzymes and other blood biomarkers.
Studies by Pizarro et al., 1999, Olivares et al., 2001, Araya et al., 2001, Araya et al., 2003a indicate that the concentration of soluble copper in the stomach is an important determinant of the GI effects of copper. The study by Araya et al. (2003a) further demonstrates that the total amount or dose of copper in the stomach is also a determinant of the GI effects of copper. Thus, the most sensitive endpoint for copper toxicity in humans (acute, reversible GI symptoms) is a function of both the amount and concentration of copper in the stomach at a particular moment in time.
The paradox of acute toxicity occurring at lower exposure levels than chronic toxicity presents a challenge for establishing acceptable exposure levels, such as soil cleanup criteria, where the aim is to protect individuals who will be exposed repeatedly on a long term basis. One scenario for which it might be necessary to develop an acceptable exposure level for copper is for soil in the vicinity of copper smelters, where copper levels can be substantially elevated relative to other contaminants. At such sites, copper in soil may be sufficiently elevated to elicit GI symptoms, particularly in young children who are more likely to engage in behavior associated with incidental soil ingestion than older children and adults. Although GI symptoms following ingestion of copper in soil have not been documented, this may be due in part to the non-specific nature of GI symptoms, which could also be caused by, and therefore misattributed to, many factors other than copper. In this analysis we present an approach for determining a remedial action criterion (RAC) for copper in soil that is protective against the gastrointestinal effects of copper.
Section snippets
Overall approach
A RAC for copper should represent a soil concentration, in mg/kg, at which there is no appreciable risk of experiencing GI symptoms, i.e., a soil concentration at which any increase in GI symptoms due to ingestion of copper from soil is indistinguishable from the typical background incidence of GI symptoms. Given that the gastrointestinal effects of copper are a function of the concentration of copper in the stomach, the RAC should be based on the concentration of soluble copper in the stomach
Results
Table 2 shows soil copper concentrations corresponding to a 2.5, 5 and 10 percent probability of experiencing GI symptoms in any given hour, as well as the corresponding probability of experiencing GI symptoms in any given day, and the predicted annual number of GI symptom episodes, assuming an exposure frequency of 180 days. Note that the hourly and daily probabilities of experiencing GI symptoms are equivalent to percentiles in the distribution of hourly and daily RACs, respectively. This
Discussion
Health-based soil cleanup criteria, such as RACs, are derived to represent a soil concentration that individuals can be exposed to repeatedly, on a chronic basis, with a negligible risk of experiencing adverse health effects. Such values are typically based on a reference dose (RfD) from a study involving repeated, chronic exposure to the chemical of concern. Because the acute effects of copper occur at lower exposure levels than chronic effects, this standard paradigm would not necessarily
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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