Acute Toxicity In Humans

There is a wide range of acute toxic effects associated with copper ingestion. Most of them represent accidental intake of contaminated foods or fluids or deliberate ingestion of large amounts of copper salts with suicidal purpose (21-24). This has led to the description of a range of responses, starting with vomiting, diarrhea, and abdominal pain to extreme cases of multiple-organ failure, shock, and death. In recent years, attention has focused to the early toxic effects that copper may elicit, mainly when it is ingested in drinking waters. Acute responses originate in the stomach and depend on copper ions that stimulate receptors, which, in turn, stimulate the vagus nerve eliciting a reflex response of nausea/vomit (25-27). When the copper dose is somewhat larger, in addition to the vagal response, direct stimulation of the hypothalamic vomit center triggers retching and vomiting. The mechanism to explain diarrhea associated to larger copper doses is not well understood.

To characterize the early acute responses to copper exposure, the copper concentration at which gastrointestinal symptoms appeared (nausea, vomiting, abdominal pain, and diarrhea) were assessed, following a "worst-scenario" design in apparently healthy adult volunteers (28). In these studies, including both genders and ages from 18 to 60 yr the NOEL was 2 mg Cu/L and the lowest observed adverse effect level (LOAEL) was 4 mg Cu/L. The first and most frequent symptom reported was nausea, which was transient, appeared within 5 min after ingestion, and did not repeat. Analysis of copper doses in water vs responses showed that in testing up to 12 mg Cu/L, close to a half of the subjects did not report symptoms. The incidence of vomiting was 11.5%; it first appeared at 6 mg/L, with a twofold increase between 10 and 12 mg/L. Interestingly, diarrhea and abdominal cramps were rare within the range of concentrations studied. Because nausea is a nonspecific response that many factors may modulate, the same volunteers were reassessed for intraindividual variability, receiving, on a second opportunity, the copper concentration at which they first reported symptoms. This showed that a large proportion (87.5%) of subjects confirmed their "threshold" concentration when this was 10 or 12 mg Cu/L. Instead, only 44.4% of them confirmed the positive responses when their "threshold" was 4 or 6 mg Cu/L. These data are relevant when assessing the safety of drinking waters. Using the dose-response curve and the 95% confidence limits, the copper concentration at which 5% of the population would respond was 2.0 and 4.2 mg Cu/L, depending on whether the first or confirmed nausea response was used for calculations.

The "worst-scenario" design used to calculate a dose-response curve required an overnight fasting and that the volunteers ingest a fixed volume of 200 mL distilled deionized water containing graded amounts of copper sulfate, all of which is not a common practice in daily life. For this reason and after completion of the first set of trials, the same subjects were invited to participate in a second set of sessions aimed at evaluating whether and how concentrations defined as confirmed threshold modified when copper was delivered in an orange-flavored drink. This was defined as a common breakfast drink. In these conditions, subjects reporting nausea dropped from 54% to 18%. The shift to the right of the dose-response curve was expected because the orange drink contained numerous potential copper binders. The lowest concentration of copper associated with nausea was 8 mg/L (28).

During these studies. all subjects who tasted the copper in the test solution described it as metallic, bad, disgusting. With the hypothesis that the capacity of tasting copper in the test solution would increase the rate of response, the same subjects underwent an additional set of trials aimed at determining the individual's threshold for tasting copper in solution. No relationships were found between tasting and outcome report, thus disproving the hypothesis. Zacarías et al. assessed in detail the curves of tasting; dislike and rejection of solutions containing graded concentrations of copper (unpublished observations). It is interesting that at low copper concentrations (2 and 4 mg Cu/L), the curve of rejection of copper sulfate in water runs very close to the curve of nausea (Fig. 1).

To further characterize the early adverse responses to copper taking into account variables that may influence intravariability and intervariability of the response, an international protocol including apparently health adult volunteers from the United States, North Ireland, and Chile was conducted.

Fig. 1. Taste, "dislike," nausea, and vomiting curves in apparently healthy volunteers after drinking graded amounts of copper sulfate in water or an orange drink.

Nausea was confirmed to be the earliest and most frequent response after ingestion of copper sulfate after overnight fasting. Using the pool data, an acute NOAEL was calculated at 4 mg Cu/L (28a).

In the above-discussed studies, we assessed the effects of administering a single bolus of copper delivered in water. There are few surveys of controlled copper ingestion during nonexperimental short-term trials. In a pioneer study, Pizarro et al. evaluated women who lived in Santiago, Chile, and who drank waters containing 0, 1, 3, or 5 mg elemental Cu/L (as copper sulfate) for 15 d. Results showed that consumption of waters with concentration >3 mg elemental Cu/L resulted in a significant increase of symptoms reported (nausea, vomiting, abdominal pain, and diarrhea) (29). Olivares et al. evaluated infants fed with formula bottles prepared with water containing 2 mg Cu/L during their first year of life (30). Children grew normally and exhibited normal liver function parameters throughout the study period; no changes on diarrhea or other illnesses were detected. The safety of this value, established by WHO as a provisional safe guideline for copper in drinking water, was again confirmed in children and adults in a large community survey recently finished (Araya et al., unpublished). In another recent field survey during which 1600 adults drank daily fluids prepared with waters containing graded copper concentrations, gastrointestinal symptoms significantly increased at 4 mg Cu/L (Araya et al., unpublished).

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