Non-essential Elements

1. Non-essential Elements There are many metals that have been shown to be essential trace elements There are also a number of metals that have no known biological function Exposure to some of these non-essential metals can have adverse health consequences

2. Metal Toxicity Different metals show toxicity at different concentrations The type of toxicity is defined by the relative level of exposure

3. Dose-response curvenon-essential elements For toxic metals the dose-response curves looks different than those seen for essential metals Since there are no beneficial effects at any level for a toxic metal, the only questions are: how low a concentration will lead to harmful effects? how rapidly will harmful effects become lethal effects with increasing concentrations?

4. Human impact on element availability Various human activities have led to changes in the levels and in the availability of many elements Most of these elements are not particularly toxic, even at these higher exposure levels However, exposure to certain metals can be quite toxic

5. Toxic Metals for Humans All metals can become toxic at sufficiently high levels however certain metals have no beneficial effects and show toxic effects at relatively low concentrations It is not just the identity of the metal, but also the chemical form and the oxidation state that dictates the toxicity in humans

6. Cadmium levels in non-contaminated foods Many foods contain “natural” levels of metal ions, some of which can be harmful if ingested in sufficient quantities

7. Effects of chronic cadmium exposure • Chronic exposure to even moderate levels of cadmium salts can lead to: • kidney failure • bone diseases • respiratory effects • carcinogenesis

8. Mercury Toxicity • Mercury is highly toxic in all forms: • mercury vapor • mercury salts • alkyl mercury Of these, alkyl mercury is the most toxic form because it is most easily absorbed Various marine organisms can metabolize mercury salts into different alkyl mercury forms Organomercury cycle in marine organisms

9. Lead Toxicity • Lead is another highly toxic metal that can lead to: • inhibition of heme synthesis • damaged central nervous system • kidney damage • impaired reproduction

10. Aluminum levels While aluminum can be toxic at higher levels, it is considerably less toxic than either mercury or lead In fact, aluminum is found at easily measurable levels in various biological fluids and tissues

11. Aluminum Toxicity However, at high levels aluminum has the potential to cause a number of health problems

12. Chromium Toxicity Chromium is another metal ion that can be highly toxic, especially in its highest (+6) oxidation state This form can easily be taken up by cells and then reduced to the slowly exchanging +3 oxidation state Uptake and reduction of chromate Once chromate is distributed to the various cellular compartments it will bind to different targets and then be reduced to the substitution inert +3 oxidation state This tightly bound form will inhibit enzyme activities and disrupt DNA replication

13. Metal Diseases Essential trace metals can also cause malfunctions and diseases when present in excess, but also when deficient * * *

14. Iron Diseases Excess Iron Hemochromatosis is an iron storage disorder that results from defects in the HFE gene. The protein encoded by this gene is a membrane protein that regulates iron absorption by controlling the interaction of the transferrin receptor with transferrin. The clinical features of this iron overload disorder include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. Iron deficiency Iron depletion causes the amount of stored iron in ferritin to be reduced, but has no immediate effect on the functional iron. Anemia occurs when the dietary intake or absorption of iron is insufficient, and hemoglobin cannot be formed.

15. Copper Deficiencies Dietary deficiencies can lead to diminished Cu levels that will impact a number of important Cu-requiring enzymes

16. Copper Metabolic Diseases Different genetic diseases can affect copper levels, leading to either an excess or a deficiency in copper availability Wilson diseasecauses the body to retain copper. The liver of a person with Wilson disease does not release copper into bile. As the intestines absorb copper from food, copper builds up in the liver and injures liver tissue. Eventually, the damage causes the liver to release the copper into the bloodstream, which then carries the copper throughout the body. The disease is treated with lifelong use of D-penicillamine that helps remove copper from tissue, or zinc acetate, which stops the intestines from absorbing copper and promotes copper excretion. Menkes diseaseis a genetic disorder of copper metabolism which follows a progressively degenerative path involving several organs of the body but especially the brain. It is caused by failure of the copper transport systems within the cell and then across the cell membrane. Because of the failure of this transport system, copper is unavailable to various cells where it is essential for the structure and function of various enzymes that control the development of hair, brain, bones, liver and arteries.

17. Menkes diseasecopper and ceruloplasmin levels Menkes disease is caused by a defect in the production of ceruloplasmin No new ceruloplasmin is produced at birth, leading to a rapid decline in both the protein levels and serum copper levels

18. Zinc Deficiencies Information about severe zinc deficiency was derived from the study of individuals born with acrodermatitis enteropathica, a genetic disorder resulting from the impaired uptake and transport of zinc. Although dietary deficiency is unlikely to cause severe zinc depletion in individuals without a genetic disorder, zinc malabsorption or conditions of increased zinc loss such as severe burns or prolonged diarrhea, may also result in severe zinc deficiency. The symptoms of zinc deficiency depend on the extent of the deficiency

19. Zinc Neurotoxicity Zinc is one of the most abundant transition metals in the brain. A substantial fraction (10–15%) of zinc in the brain is located in presynaptic vesicles in a loosely bound state. This vesicle zinc is released with neuronal activity or depolarization, probably serving physiologic functions. However, with excess release zinc may translocate and accumulate in postsynaptic neurons, which may contribute to selective neuronal cell death. Intracellular mechanisms of zinc neurotoxicity may include disturbances in energy metabolism, increases in oxidative stress, and activation of apoptosis. low excess Zn exposure leads to binding by Hsp70 Zn can inhibit glycolysis thus depleting ATP and leading to cell necrosis Zn can also activate protein kinases (PKC) leading to oxidative stress Zn can also lead to activation of caspases which triggers apotosis Molecular Neurobiology, 24, 99-106 (2001)

20. Metal Carcinogens Certain metal salts have been shown to induce tumor formation in mice Their carcinogenic activities have been classified based on the levels of metals needed to induce tumor growth

21. Summary • Metal toxicity can be acute (high exposure level) or chronic (low exposure over long periods) • Metal toxicity depends on the element, its chemical form and its oxidation state • Cadmium, mercury, lead, aluminum and chromium can all be highly toxic • Essential metals can also cause health problems either when they are deficient or when present in excess • Metabolic disorders can lead to defects in iron, copper and zinc availability • Exposure to some metals has been shown to lead to higher incidents of certain cancers