Copper in Drinking Water (2000) / Chapter Skim
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5 Health Effects of Excess Copper
5 Health Effects of Excess Copper
Pages 78-126
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From page 78... ...
Effects on other target organs, such as the liver, in subjects following highdose chronic exposure and in sensitive populations are considered. Toxicity data from animal studies are presented, and the use of animal models for studying the mechanism underlying the toxicity of copper in humans is discussed.
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From page 79... ...
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From page 82... ...
82 ._ ¢ En In a' o v Cat a)
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From page 83... ...
Acute copper toxicosis, manifested by hemolysis, headache, febrile reactions, prostration, and GI symptoms, was observed in one child after a solution containing copper sulfate was applied to burned skin during a debridement procedure (Holtzman et al.
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From page 84... ...
1984~. Family members had increased copper concentrations in hair, but not blood.
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From page 85... ...
A1though people with high concentrations of copper in their drinking water were slightly more likely to report becoming ill at some point during the study, there was no significant association of tap-water copper concentration and GI symptoms. The committee had difficulty in determining how to use the available epidemiological data.
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From page 86... ...
is being conducted to determine the dose-response relationship more precisely for the GI effects of copper in drinking water (ICA, unpublished material, Oct.
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From page 87... ...
1993~. In that case, the pathological picture is similar to that seen in Wilson disease or the various childhood cirrhosis syndromes associated with excess copper exposure.
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From page 88... ...
The CNS can also be a target of chronic copper toxicity. Generally speaking, reports of neurotoxicity from chronic copper exposure have been limited to humans with Wilson disease.
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From page 89... ...
They reported that mean serum copper concentrations were highest in the patients with malignant tumors. It is important to note that the serum concentrations of copper were measured after diagnosis and might have been due to increased ceruloplasmin.
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From page 90... ...
In this prospective study, copper concentrations in 46 women with breast cancer were compared with a stratified random sample of 38 women. The adjusted odds ratios did not suggest an increased risk for breast cancer due to copper exposure, although when copper levels were stratified, the highest exposure group did have a significantly increased relative risk.
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From page 91... ...
. Genetic defects in copper metabolism might confer sensitivity to excess copper exposure (also reviewed in Chapter 4~.
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From page 92... ...
A second hypothesis is that heterozygosity for Wilson gene defect combined with abnormal copper handling and increased copper exposure (Brewer in press) results in an increased sensitivity to copper in early childhood and underlies TIC, ICC, and many of the ICT cases.
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From page 93... ...
The ICT data again suggest that a defective gene is present that makes infants and children unusually susceptible to high copper intake. Although the majority of TIC and ICC cases appear to be associated with high concentrations of copper in milk, nearly all of the ICT cases associated with increased copper exposure appear to be associated with increased copper concentrations in water rather than in milk.
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From page 94... ...
With the exception of suicide attempts with copper salts, there is little evidence that low molecular weight copper increases significantly as a consequence of high dietary copper intake. Indeed, even in Wilson patients who have increased copper concentrations, hemolysis does not occur in the absence of hepatic necrosis.
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From page 95... ...
Levels of intake can be exceeded, particularly in cases where the drinking water contains high copper concentrations. Those factors should be kept in mind when human studies are contrasted with experimental data in animal studies of chronic exposure to copper (see Table 5-2~.
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From page 98... ...
In rabbits, chronic exposure to copper in drinking water (10 mg of coppery of body weight) was associated with marked hepatic toxicity, whereas dogs exposed to copper gluconate equivaTent to 8.4 mg of copper~g of body weight in feed had no toxic effects (Shanaman 1972; Shanaman et al.
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From page 99... ...
1992~. Total serum copper concentrations in the dogs are one-third those in the rat, and plasma ceruloplasmin concentrations are 8fold less in the dog than in the rat (Montaser et al.
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From page 100... ...
Kidneys of rats consuming excess copper at 92 mg of copper/kg per day had an increased number and size of protein droplets in the epithelial of the renal cortical tubules (NTP 19931. Comparison of toxicity following exposure in drinking water and feed is a difficult task given the differences in consumption of copper in the two exposure paradigms.
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From page 101... ...
There was a dose-related decrease in liver weights (NTP 1993~. In mice receiving excess copper at 188 mg of copper/ kg per day, there was a dose-related increase in hyperplasia, with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach.
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From page 102... ...
Periods of starvation can be teratogenic or embryo lethal in many species. Neurotoxicity Generally speaking, neurotoxicity from copper seems to occur only in humans with Wilson disease; however, in various animal models in which copper ingestion is increased, some neurological effects have been observed.
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From page 103... ...
. In contrast, daily administration of 1,250 mg of copper sulfate/L of drinking water (0.125%; equivalent to about 46 mg of copper/ kg of body weight per day)
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From page 104... ...
Mechanisms and Animal Models for Copper Toxicity Mechanism of Acute Copper Toxicity Although the symptoms associated with acute and chronic copper toxicity have been well defined in humans, the mechanisms of copper toxicosis and the concentration at which toxicosis occurs remain poorly understood. A number of investigators have studied the mechanism of the gastric response to excess copper in an effort understand the implications of acute exposure to excess copper in drinking water.
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From page 105... ...
support its role as a copper transporter involved in the intracellular trafficking of copper in hepatocytes. In LEC rats and Wilson disease, copper accumulation is associated with a defective copper-transporting P-type ATPase, resulting in reduced biliary excretion of copper ~Iuramatsu et al.
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From page 106... ...
1998~. Chronic copper toxicity in LEC rats is associated with the uptake of copper-loaded metallothionein (MT)
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From page 107... ...
However, the secretion of ceruloplasmin from the cultured cells was not reduced in hepatocytes from LEC cells compared with controls. Additional studies confirmed that the genetic defect in LEC rats did not alter the biosynthetic and secretory pathways of ceruloplasmin, and that the intracellular copper concentration did not regulate the synthesis and processing of ceruloplasmin in the cultured hepatocytes.
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From page 108... ...
In LEC rats, serum ceruloplasmin concentrations are almost normal, and the oxidase activity of ceruloplasmin, which represents holo-ceruloplasmin, is low in Wilson disease. Hepatocellular carcinoma occurs frequently in the LEC rat, and cirrhosis does not.
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From page 109... ...
Autosomal recessive Severely high Low Low Normal High High Low Almost normal Increase T LOW Similar to Wilson disease Hepatocellular carcinoma Effective liver accumulation of copper. When copper and retrorsine were subsequently administered, the rats developed severe liver damage with retention of copper.
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From page 110... ...
1996~. Hepatic copper concentrations in copper toxicosis-afflicted Bedlington terriers range from 1,000 to 10,000 Agog of dry weight (Owen et al.
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From page 111... ...
In sensitive human populations, the major target of chronic copper toxicity is the liver. In Wilson disease, neurological toxicity also occurs.
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From page 112... ...
Studies should be conducted in the LEC rat to determine the role of ATP7B in copper transport and the cellular and molecular mechanisms of tissue injury resulting from copper accumulation. LEC rats should be outbred with Long-Evans rats to create rats heterozygous for the ATP7B transporter.
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From page 113... ...
1975. Ineffectiveness of hemodialysis in copper sulfate poisoning.
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From page 114... ...
1998. Physiologic function of the Wilson disease gene product, ATP7B.
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1965. Acute copper sulfate poisoning.
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1967. Copper sulfate-induced hemolytic anemia.
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From page 117... ...
1984. Side effects of 58 years of copper sulfate of the Fairmont Lakes, Minnesota.
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From page 118... ...
1986. Inherited, chronic, progressive hepatic degeneration in Bedlington terriers with increased liver copper concentrations: clinical and pathologic observations and comparison with other copper-associated liver diseases.
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1998. A marked increase in free copper levels in the plasma and liver of LEC rats: an animal model for Wilson disease and liver cancer.
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From page 120... ...
1997. Copper and iron-induced oxidative damage in non-tumor bearing LEC rats.
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From page 121... ...
1998. A high expression of heme oxygenase-1 in the liver of LEC rats at the stage of hepatoma: the possible implication of induction in uninvolved tissue.
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~ u~. copper storage disease of the liver and chronic dietary copper intoxication in two further German infants mimicking Indian childhood cirrhosis.
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From page 123... ...
1998. Targeting oftetrathiomolyb~ate on the copper accumulating in the liver of LEC rats.
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1997. Copper in plasma reflects its status and subsequent toxicity in the liver of LEC rats.
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From page 125... ...
1995. Disordered copper metabolism in LEC rats, an animal model of Wilson disease: roles of metallothionein.
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From page 126... ...
1994. The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.
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