Zinc Toxicity in Humans, Esquemas y mapas conceptuales de Biología

¡Descarga Zinc Toxicity in Humans y más Esquemas y mapas conceptuales en PDF de Biología solo en Docsity! Zinc Toxicity in Humans Jerome Nriagu, School of Public Health, University of Michigan ª 2007 Elsevier B.V. All rights reserved. Introduction Functions of Zinc in Humans Epidemiology Acute Health Effects Chronic and Subchronic Toxicity Potential for Zinc Accumulation Further Reading Introduction In dealing with zinc’s essentiality/toxicity (Dr. Jekyll and Mr. Hyde) duality, biological systems have developed the homeostatic ability to tightly regulate the zinc levels through a complicated framework for import and export, transport and distribution and sensing of zinc status to ensure that zinc does not participate in toxic reactions. In spite of the thousands of papers that have been published on biological effects of zinc, the challenge of quantifying the range of exposure doses that constitute zinc deficiency versus excess remains unresolved. Recent studies with better design and more sensitive methods point to a con- siderable overlap between what has generally been considered to be the essential dose and toxic dose, sug- gesting that the dose-response curve for zinc may not be a ‘‘U’’ but a ‘‘V’’. Although zinc is not involved in cellular redox cycle and has traditionally been regarded as relatively non- toxic, recent studies increasingly show that free ionic zinc (Zn2þ) is a potent killer of neurons, glia and other cell types. Zinc concentrations in the brain are maintained within a narrow range of 600-800 ng/L with deviations substantially above and below this range being procon- vulsive and cytolethal respectively. Free zinc ion may be much more toxic biologically than is generally realized. The physiologically optimal Zn2þ concentration in eukaryotic cells is around 10 ng/L and when the zinc level falls below 0.06 ng/L apoptosis can be triggered but when the level rises above 60 ng/L toxicity can ensure. The evolution of biomolecules to scavenge the zinc ions was crucially important in ameliorating the cellular toxicity and facilitating the myriad cellular uses for zinc. Functions of Zinc in Humans Zinc is extraordinarily useful in biological systems. It is involved in many biochemical processes that support life and required for a host of physiological functions including normal immune function, sexual function, neurosensory function such as cognition and vision. Numerous proteins, enzymes and transcription factors depend on zinc for their function. Zinc is an essential component of hundreds of proteins and metalloenzymes including alkaline phosphatase, lactate dehyrogenase, carbonic anhydrase, carboxypeptides, and DNA and RNA polymerases found in most body tissues. Zinc plays specific and important catalytic, co-catalytic and structural roles in enzyme molecules and in many other proteins and biomembranes. A well-known example of the structural role of zinc in cellular and subcellular metabolism is the zinc finger motif, ubiquitous in tran- scription proteins. The configuration of zinc fingers, critical to DNA binding, is determined by the single zinc atom at their base. The linking of zinc fingers to corresponding sites on the DNA initiates the transcription process and gene expression. Motifs similar to zinc fingers have been identified in nuclear hormonal receptors including those for vitamin D, estrogen and testosterone. Zinc plays an important role as ionic signaling in large number of cells and tissues. Many individual zinc-secret- ing cell types are known throughout the body, including the CNS neurons, submandibular salivary glands (mod- ified to venom glands in snakes), prostate epithelial cells, pancreatic exocrine cells, pancreatic -cells, mast cells, granulocytes, Paneth cells in the intestine, and pituitary cells. The biological and physiological roles of these somatic zinc signals are still poorly understood. Zinc-binding proteins account for nearly half of the transcription regulatory proteins in the human genome, and during the past two decades, well over 2000 zinc- dependent transcription factors involved in gene expres- sions of various proteins have been reported. In addition to being critical enzymatic cofactors involved in regula- tion the DNA transcription, other important functions of zinc in humans include (a) cell proliferation, differentia- tion and apoptosis; (b) immune response onset and regulation, (c) protein synthesis; (d) DNA metabolism and repair; (e) energy metabolism; (f) vitamin A metabo- lism; (g) insulin storage and release; (h) spermatogenesis and steroidgenesis; (i) neurogenesis, synaptogenesis and neuronal growth; (j) sequestration of free radicals and 1 protection against lipid peroxidation; (k) cellular division; (l) signal messenger and neuro-transmission; (m) stabili- zation of macromolecules. The ubiquity and extreme versatility of zinc in human proteomics speak to the fact that zinc deficiency or excess may result in the impairment of many metabolic and organ functions. It is not clear whether these functions are hierarchical in terms of zinc utilization, in other words, whether all zinc-dependent functions are affected to the same extent or some pathways are partially compromised for the sake of homeostasis as zinc becomes increasingly limit- ing. One thing is clear, however. Zinc insufficiency or excess can moderate a cascade of metabolic processes that adversely affect the health of human beings and other organisms. Epidemiology In general, well-conducted epidemiological studies risks of exposure to zinc in the environment with adequate characterization of the exposure matrices are lacking, and the available data are not adequate data to establish an association between environmental exposure to zinc and health outcomes. Inhalation exposure to zinc chloride fume occur primarily during military or civilian fire-drill exercises. An accidental ignition of several smoke gen- erators at a storage site led to the poisoning of 70 people, ten of whom died. Numerous cases of accidental and intentional (self- harm) ingestion of zinc salts have been reported. A few of these accidental exposures have resulted in death but debilitating sequelae is often the recorded consequence, such as vomiting, diarrhea, red urine, icterus (yellow mucous membrane), liver and kidney derangement and anemia. At present, 10 pesticides containing zinc salts (includ- ing the oxide, sulfate, chloride and phosphide) are commercially available in the United States. These zinc salts are used as herbicides to control the growth of moss on patios, walkways, lawns and structures. Zinc oxide is used as a bacteriostat and as industrial preserva- tives, incorporated into carpet fibers to inhibit bacterial and fungal growth and as pressure treatment to preserve cut lumber. The pesticidal (environmentally dissipative) use exposes a large number of people to zinc but there is no indication that the levels of exposure constitute a significant health hazard to the people or the environment. Millions of people are currently being exposed to various levels of zinc as food supplements and additives, as medicines, disinfectants, antiseptic and deodorant pre- parations and in dental cement. The risks associated with zinc exposure from these routes have become a matter of intense debate in the annals of toxicology and human nutrition (see Zinc Deficiency in Human Health). There are inherent difficulties in estimating zinc requirements for humans, with a number of physiological, dietary and environmental factors affecting various popu- lations. Strategies that have been used to estimate human requirements include the metabolic balance studies, in which zinc intake was compared with zinc excretion in the urine and faeces and factorial calculations that account for the zinc required for growth, losses (including zinc lost in sweat, shed hair and skin, semen and milk) and bioavailability. The factorial estimates for zinc require- ments are outlined in Table 1. Growing infants, children, growing adolescents, and pregnant and lactating mothers require more zinc per kilogram of body weight than do mature adults. The data in the table may be compared with reported averages for dietary intake of zinc vary from 5 to 20 mg/d. While average intakes may be ade- quate for a segment of any given population, every community has groups that are at risk of zinc deficiency. Values for the recommended dietary allowance should be compared with the reference dose (RfD) for zinc, which is an estimate of the daily exposure to which human population may be continuously exposed over lifetime without an appreciable risk of adverse health effect and is aimed at protecting sensitive subpopulations. The US Environmental Protection Agency (US EPA) has set an RfD of 0.3 mg/kg-day for zinc, based on reported lowest observed adverse effect level (LOAEL) from a clinical study of the effects of oral zinc supplementation on copper and iron status. This RfD corresponds to 21 mg zinc for a 70-kg male and 18 mg for a 60-kg female and is higher than the recommended acceptable daily intakes recommended by the WHO in some instances. On the other hand, the US Food and Nutrition Board has set the tolerable upper intake level (UL) at 40 mg/d for adults older than 19 years. The UL is another form of toxicity risk assessment value designed to protect 97–98% of the population. The apparent conflicts in RDA, RfD and UL values above primarily reflect the huge uncertainties in our ability to associate zinc status with normal states of human health and in detecting mild to moderate zinc deficiency and toxicity endpoints. A comparison of the RDA with RfD nevertheless points to the fact that there is little margin between the safe and unsafe doses for zinc. The narrow margin of safety raises a number of concerns about the current framework for managing the risks of zinc deficiency in human populations. The growing ten- dency to add zinc to increasing number of food items raises the issue of cumulative exposure of zinc additives in relation to the RDA. New food preparation, processing and preservation technologies can affect the zinc bioavail- ability and significantly change the amount of food one needs to consume to meet one’s daily zinc requirement. 2 Zinc Toxicity in Humans ingested high doses of zinc. Microcytic anemia and decreased blood platelets have been reported as a resulted of sustained of hands to zinc chloride solution. Pulmonary Toxicity Ingestion of correction fluid by an asthmatic patient brought about an acute episode of bronchospasms and severe oropharyngeal and laryngeal inflammation which led to stridor and dysphonia. Swallowing of one table- spoon of soldering flux (containing 22.5% zinc chloride) by a child triggered severe coughing and wheezing in addition to the features of gastrointestinal toxicity. Hepatic Toxicity Excess copper and zinc levels in a small number of Cree and Ojibwa-Cree children have been associated severe chronic cholestatic liver disease progressing to end-stage biliary cirrhosis in these children. Since there was no data to indicate that any exposure to excess zinc had occurred in these children, it could be that the effects might have been due to an inborn error of metal metabolism, second- ary dietary or environmental factors, or genetic factors. Nephrotoxicity Microscopic hematuria unaccompanied by renal failure and mild albuminuria have been associated with ingestion of high doses of zinc. Neurotoxicity Ingestion of high levels of zinc have resulted in lethargy, lightheadedness, staggering, difficulty in writing clearly, anxiety, depression, somnolence and comatose. Hepatotoxicity Transiently increased liver enzyme activities have been linked to severe gastrointestinal corrosive effects of high- dose ingestion of zinc. Cancer Zinc has not been shown to be a human mutagen or carcinogen. Zinc deficiency impairs the molecular mechanisms designed to protect against DNA damage, influences genetic stability and function, enhances the susceptibility to DNA-damaging agents and furthermore affects cellular differentiation, proliferation and apoptosis. This has led some people to speculate that zinc deficiency is a potential risk factor for cancer. The link between zinc deficiency and human cancer remains tenuous, however. Chronic and Subchronic Toxicity Ingestion of zinc and zinc-containing compounds can result in a variety of chronic effects in the gastrointestinal, hematological and respiratory systems along with alterations in the cardiovascular and neurological systems of humans. The intake of zinc in the range of approximately 100–300 mg/d (doses likely to induced chronic toxicity) is common among people using zinc-containing supple- ments and oral zinc medicines (self-medication, prescribed by a physician or traditional remedies). Prolonged zinc exposure via these routes has been shown to result in copper deficiency characterized by hypocupremia, anemia, leucopenia and neutropenia; some subjects additionally report headache, abdominal cramps and nausea. The antioxidant enzyme Cu-Zn- superoxide dismutase (SOD) is said to be very sensitive to changes in plasma Zn/Cu ratio and alterations in SOD activity with zinc supplementation may result in excess free radicals that are damaging to the cell membrane. Studies have also noted some competitive interaction between zinc and iron that can result in decreased serum ferritin and hematocrit concentrations especially in women. A number of studies have been conducted to examine the effects of zinc intake on blood lipid levels. The lowest dose of zinc that affects lipid metabolism is ill- defined, but it was approximately twice the US recom- mended daily allowance. Doses of zinc of 50–300 mg in excess of dietary amounts generally have potentially harmful effects on lipid metabolism. The majority of these studies show that zinc supplements and therapeutics has recently been shown to adversely affect the serum cholesterol balance, with generally an increase in low- density lipoprotein (LDL) cholesterol and a decline in high-density lipoprotein (HDL) cholesterol. Under normal circumstances, the major route of zinc excretion is via the pancreas. Prolonged consumption of supplements may lead to an accumulation of zinc and impairment of the pancreatic function, resulting in increased release of amylase, lipase and alkaline phospha- tase into the blood stream. An interesting body of scientific literature suggests that zinc is a neurotoxin. Zinc is selectively stored and released from presynaptic vessels of neurons found pri- marily in the mammalian cerebral cortex. Because the zinc-releasing neurons also release glutamate, they are sometimes referred to as ‘‘gluzinergic’’ neurons. The zinc- and glutamate-secreting terminals are conspicu- ously accumulated in the vast network of neocortex and limbic structures (amygdala and septum). Zinc can mod- ulate the overall excitability of the brain possibly through its effects on glutamate, -aminobuthric acid (GABA) receptors of this network. The gluzinergic neutrons may play a role in the synaptic plasticity that underlies learn- ing and memory – the plasticity of young mammalian brain is frequently accompanied by changes in innerva- tion by zinc-containing neurons. The zinc produced synaptically or from other dynamic sources (such nitric oxide-mediated release from metallothioneins) promotes Zinc Toxicity in Humans 5 neuronal death by inhibiting cellular energy production by interfering with a number of processes such as mito- chondrial electron transport chain, the tricarboxylic acid cycle and enzymes of glycolysis. There is evidence to suggest that synaptically released zinc contributes to excitotoxic brain injury after seizures, stroke and brain trauma. Studies with molecular biomarkers suggest that mater- nal zinc supplementation (in the presence of methyl- containing substances such as folic acid, vitamin B12 and choline) can have a significant influence on mechanisms of epigenetic regulation, imprinting and specific gene expressions. The reprogramming of some fetal genes allows the effects of zinc deficiency or copper deficiency secondary to excessive zinc supplementation to become cross-generational. The review above suggests that sus- tained exposure to doses of zinc found in supplements and medicines carry a health risk attributable to interference with the metabolic cycles of copper and other essential elements, impairment of the immune and pancreatic functions, and dysregulation of epigenome. The role of zinc in the pathogenesis of Alzeimer’s disease (AD) is gaining interest since it was reported that zinc can precipitate amyloid beta-peptide (A) and induce -amyloid aggregation in senile plaque. The zinc theory of AD is based on the fact that A deposits are limited to the neocortex where the highest zinc concen- tration occurs, even though A is ubiquitously produced in the brain. Early-phase clinical trials show that zinc chelation inhibits A-plaque deposition. Furthermore, therapeutic strategies designed to remove zinc bound to proteins, in particular to A, with the use of metal- protein-attenuating compounds (MPACs), such as clio- quinol, have resulted in significant reduction in the cognitive decline in patients with moderately AD. This drug, however, led to the appearance of subacute myelo- optic neuropathy, which is a condition strictly related to zinc deficiency and had to be withdrawn. Neocortical tissue affected by Alzheimer’s disease tends to accumulate zinc to high levels, suggesting that besides the direct effect of zinc on amyloid aggregation, zinc may also contribute to the pathology of the disease through other pathways. The abnormal form of the prion protein (PrP) is believed to be responsible for the Creutzfeldt-Jakob dis- ease, bovine spongiform encephalopathy and other transmissible spongiform encephalopathies. One of the peptides containing the human PrP106-126 residues share a number of biophysical properties with the amy- loid  (A) peptide of Alzheimer’s disease. For instance, the A residues 25-35 of Alzheimer’s disease are similar to the PrP106-126 core sequence and both play an impor- tant role in stabilizing the A aggregates that induce neurotoxicity. There is a growing body of evidence to suggest zinc modulates the A aggregation and the neu- rotoxic properties of PrP106-126. Interactions with a number of trace elements can affect the absorption, distribution, metabolism and excretion of zinc and hence the zinc’s toxicity. Exposure to higher than normal levels of zinc can induce copper deficiency and anemia and may influence the activity of superoxide in humans, as noted previously. Zinc interaction with cad- mium tends to be protective in that zinc reduces the organ levels of cadmium under normal circumstances. Exposure to high levels cadmium (high Cd/Zn ratio) may cause changes in inter-organ distribution of zinc with an accu- mulation of zinc in the kidney and a deficiency in other organs. Under severe limitation, the cells increasingly rely on cadmium to meet their zinc requirements, thereby converting cadmium into an ‘‘essential’’ trace element; this process increases the risk of cadmium toxicosis. Zinc is required for the activity of -aminolevulinic acid dehydrogenase (ALAD) activity which plays a protective role in heme biosynthesis. Both tin and zinc are said to attach to the same sites in the ALAD but the effects of changes in tin/zinc ratio on the activity of this enzyme is unknown. Prolonged exposure to high doses of zinc can lower the serum levels of manganese thereby increasing the susceptibility to autoimmune reactions. The effects of dietary zinc insufficiency or excess on blood levels of children remain equivocal. Potential for Zinc Accumulation An average 70-kg adult contains 2-3 g of zinc, making it nearly as abundant as iron. The zinc is widely distributed in the skeletal muscle, bone, brain, GI tract, liver, kidney, lung, heart, retina, pancreas, sperm and uterus. The high- est concentration ( 100 mg/kg wet weight) is found in the prostate. Concentration of zinc in whole blood is about 5 mg/L and about 5-fold less in plasma and serum. Unlike iron, there is no particular body store for zinc and metabolic zinc requirement must be met by intake of food and supplements coupled to poorly under- stood homeostatic processes. The biological half-life of zinc is about 280 days, consistent with the fact that only a small fraction (2-3 mg) of the total body burden of zinc is renewed (required) daily. The body controls the amount of zinc stored in the body by reducing the absorption and increasing excretion when intakes is increased above the metabolically set threshold. The distribution of zinc in some tissues may be regu- lated by age to some degree. Zinc concentrations increase in the pancreas, liver, and prostate but decrease in the aorta and uterus with age. Levels of zinc in the kidney and heart tend to peak at about 40–50 years of age and then decline. See also: 00002 6 Zinc Toxicity in Humans Further Reading ATSDR (1993). Toxicological Profile for Zinc. US Department of Health & Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia Cai L, Li XK, Song Y and Charian MG (2005) Essentiality, toxicology and chelation therapy of zinc and copper. Current Medical Chemistry 12: 2753–2763 CCOHS (2006) Chemical Profiles in CHEMINFO Database. Canadian Centre for Occupational Health and Safety. http://www.intox.org/ databank/documents/chemical/zincchlr/cie467.htm Elliott JL (2001) Zinc and copper in the pathogenesis of amyotrophic lateral sclerosis. Progress in Neuro-Psychopharmacological & Biological Psychiatry 25: 1169–1185 Fosmire GJ (1990) Zinc toxicity. American Journal of Clinical Nutrition 51: 225–227 Frederickson CJ, Koh JY and Bush AI (2005) The neurobiology of zinc in health and disease. Nature Neuroscience 6: 449–462 Hambidge M (2003) Biomarkers of trace mineral intake and status. Journal of Nutrition 133: 948S–955S IPCS (2006) Environmental Health Criteria 221: Zinc. International Programme on Chemical Safety. http://www.inchem.org/ documents/ehc/ehc/ehc221.htm. Accessed on July 16, 2006 Jobling MF, Huang X, Stewart LR, Barnham KJ, Curtain C, Volitakis J, Perugini M, White AR, Cherny RA, Masters CL, Barrow CJ and Collins ST (2001) Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106- 126. Biochemistry 40: 8073–8084 Kathman NCW, Sarasua SM and White MC (2003) Influence of environmental zinc on the association between environmental and biological measures of lead in children. Journal of Exposure Analysis and Environmental Epidemiology 13: 318–323 Maret W and Sandstead HH (2006) Zinc requirements and the risks and benefits of zinc supplementation. Journal of Trace Elements in Medicine and Biology 20: 3–18 Mocchegiani E, Bertoni-Freddari C, Marcellini F and Malavolta M (2005) Brain, aging and neurodegeneration: role of zinc ion availability. Progress in Neurobiology 75: 367–390 Nriagu JO, editor (1980) Zinc in the Environment, Part 2: Health Effects. Wiley, New York Oteiza PI and Mackenzie GG (2005) Zinc, oxidant-triggered cell signaling and human health. Molecular Aspects of Medicine 26: 245–255 Scheplyagina LA (2005) Impact of the mother’s zinc deficiency on the woman’s and newborn’s health status. Journal of Trace Elements in Medicine and Biology 19: 29–35 Web-based Resources Zinc Toxicity in Humans 7