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Review ArticleBiomedical Implications of Heavy Metals InducedImbalances in Redox Systems

Bechan Sharma1 Shweta Singh2 and Nikhat J Siddiqi3

1 Department of Biochemistry University of Allahabad Allahabad 211002 India2Department of Genetics SGPGIMS Lucknow 226014 India3 Department of Biochemistry King Saud University Riyadh 11451 Saudi Arabia

Correspondence should be addressed to Bechan Sharma sharmabiyahoocom

Received 28 February 2014 Revised 28 May 2014 Accepted 10 July 2014 Published 12 August 2014

Academic Editor Hartmut Jaeschke

Copyright copy 2014 Bechan Sharma et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Several workers have extensively worked out the metal induced toxicity and have reported the toxic and carcinogenic effects ofmetals in human and animals It is well known that these metals play a crucial role in facilitating normal biological functionsof cells as well One of the major mechanisms associated with heavy metal toxicity has been attributed to generation of reactiveoxygen and nitrogen species which develops imbalance between the prooxidant elements and the antioxidants (reducing elements)in the body In this process a shift to the former is termed as oxidative stress The oxidative stress mediated toxicity of heavymetals involves damage primarily to liver (hepatotoxicity) central nervous system (neurotoxicity) DNA (genotoxicity) and kidney(nephrotoxicity) in animals and humans Heavy metals are reported to impact signaling cascade and associated factors leading toapoptosisThe present review illustrates an account of the current knowledge about the effects of heavymetals (mainly arsenic leadmercury and cadmium) induced oxidative stress as well as the possible remedies of metal(s) toxicity through naturalsyntheticantioxidants which may render their effects by reducing the concentration of toxic metal(s) This paper primarily concernsthe clinicopathological and biomedical implications of heavy metals induced oxidative stress and their toxicity management inmammals

1 Introduction

Many different definitions for heavy metals have been pro-posed some based on density some on atomic number oratomic weight and some on chemical properties or toxicityThe group of heavy metals can include elements lighterthan carbon and can exclude some of the heaviest metalsOne of such definitions entails that heavy metals are thoseinorganic elements which have five times the specific gravityof water Among the heavy metals having serious healthimplications are arsenic lead cadmium and mercury [1]The accumulation of these elements can cause severe damageto mucus tissues and intestinal tract and skeletal centralnervous and reproductive systems In addition to the toxicand carcinogenic effects of some metals in humans andanimals they also play pivotal role in mediating a balancedbiological functioning of cells

Heavy metals are natural components of the earthrsquos crustThese elements are the oldest toxins known to humanshaving been used for thousands of years Potential sourcesof heavy metals exposure include natural sources (eggroundwater metal ores) industrial processes commercialproducts folk remedies and contaminated food and herbalproducts Virtually all heavy metals are toxic in sufficientquantities Because of their concentrations in the environ-ment lead mercury and arsenic are of particular interestEntering our bodies by way of food drinking water andair metals produce toxicity by forming complexes withcellular compounds containing sulfur oxygen or nitrogenThe complexes inactivate enzyme systems or modify criticalprotein structures leading to cellular dysfunction and death

The most commonly affected organ systems includecentral nervous gastrointestinal (GI) cardiovascularhematopoietic renal and peripheral nervous systems The

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 640754 26 pageshttpdxdoiorg1011552014640754

2 BioMed Research International

Ions

Hydrogenperoxide (H2O2)

Hypochloriteion (OCl minus)

ROS contain nonradicals

MoleculesH

H

H

H

Reactive oxygen species (ROS)

minus minus

Superoxideanion (O 2

∙minus)

OO

OOO

OOO

Clradical (HO 2

∙)

Hydroxyl

Hydroperoxylradical (OH ∙)

and radicals

Figure 1 Reactive oxygen species (ROS) existing in radicals andnonradicals forms

nature and severity of toxicity vary with the heavy metalinvolved its exposure level chemical and valence states(inorganic versus organic) mode of exposure (acute versuschronic) and the age of the individual Children with theirdeveloping nervous systems are particularly vulnerable toheavy metal intoxication (especially lead)

The heavy metals induced toxicity has been extensivelystudied and reported by various workers They have demon-strated that the exposure of an animal to excess concen-trations of these elements may augment production of freeradicals which may cause oxidative stress [2ndash5] In factgeneration of oxidative stress has been considered as oneof the major mechanisms behind heavy metal toxicity Theheavymetals have potential towards production of the highlyreactive chemical entities such as free radicals having theability to cause lipid peroxidation DNA damage oxidationof sulfhydryl groups of proteins depletion of protein andseveral other effects [3] The heavy metals have been foundto generate reactive oxygen species (ROS) which in turnresults in their toxic effects in the form of hepatotoxicity andneurotoxicity as well as nephrotoxicity in both animals andhumans [2 4] Some of the reactive oxygen species are shownin Figure 1Their few characteristic properties and impact oncellular systems are summarized in Table 1

This review summarizes an updated account of availableinformation on heavymetals induced imbalance in the redoxsystems in the body and their clinical and pathophysiologicalimplications as well as use of certain natural and syntheticproducts to mitigate their toxicity It illustrates toxic effects ofonly four key heavy metals such as arsenic lead cadmiumandmercury which are ubiquitous in air andwater pollutantsthat continue to threaten the quality of public health aroundthe world These elements are associated with many adversehealth effects generated through oxidative damage and dis-ease processes [5]

2 Arsenic

Arsenic is particularly difficult to characterize as a singleelement because its chemistry is really complex Arsenicoccurs in three oxidation states trivalent arsenite (As (III))

Table 1 Brief description of some reactive oxygen species (ROS)

Oxidant Description

∙O2

minussuperoxideanion

One-electron reduction state of O2 formedin many autoxidation reactions and by theelectron transport chain Rather unreactivebut can release Fe2+ from iron-sulfurproteins and ferritin Undergoesdismutation to form H2O2 spontaneously orby enzymatic catalysis and is a precursor formetal-catalyzed ∙OH formation

H2O2 hydrogenperoxide

Two-electron reduction state formed bydismutation of ∙O

2

minus or by direct reductionof O2 Lipid soluble and thus able to diffuseacross membranes

∙OH hydroxylradical

Three-electron reduction state formed byFenton reaction and decomposition ofperoxynitrite Extremely reactive and willattack most cellular components

ROOH organichydroperoxide

Formed by radical reactions with cellularcomponents such as lipids and nucleobases

RO∙ alkoxyand ROO∙peroxy radicals

Oxygen centred organic radicals Lipidforms participate in reactions Produced inthe presence of oxygen by radical additionto double bonds or hydrogen abstraction

HOClhypochlorousacid

Formed from H2O2 by myeloperoxidaseLipid soluble and highly reactive Willreadily oxidize protein constituentsincluding thiol groups amino groups andmethionine

ONOOminusperoxynitrite

Formed in a rapid reaction between ∙O2

minus

and NO∙ Lipid soluble and similar inreactivity to hypochlorous acid Protonationforms peroxynitrous acid which canundergo homolytic cleavage to formhydroxyl radical and nitrogen dioxide

pentavalent arsenate (As (V)) and elemental Arsenite is tentimes more toxic than arsenate elemental arsenic is non-toxic Arsenic also exists in three chemical forms organicinorganic and arsine gas with organic arsenic having littletoxicity whereas inorganic arsenic and arsine gas are toxicIt is widely distributed in nature and utilizes its three mostcommon oxidation numbers (+5 +3 and ndash3) to form chemi-cal complexes in body A summary of environmental sourcesof arsenic as well as their potential health effects is men-tioned in the National Research Council report on arsenicin drinking water Most major US drinking water suppliescontain levels lower than 5 120583gL It has been estimated thatabout 350000 thousand peoplemight drinkwater containingmore than 50120583gL [7] Exposure to arsenic primarily occursby ingestion but inhalation and absorption through the skinare possible Arsenic occurs naturally in seafood as nontoxicorganic compounds such as arsenobetaine which can causeelevated urine arsenic levels The lethal dose of inorganicarsenic has been estimated to be 06mgkg

About 80ndash90 of a single dose of arsenite As (III)or arsenate As (V) has been shown to be absorbed fromthe gastrointestinal (GI) tract of humans and experimental

BioMed Research International 3

animals Arsenic compounds of low solubility such as arsenicselenide lead arsenide and gallium arsenide are absorbedless efficiently than dissolved arsenic Systemic skin toxicityhas been reported in persons having extensive acute dermalcontact with solutions of inorganic arsenic [8] The airbornearsenic is largely trivalent arsenic oxide Its deposition inairways and absorption from lungs are dependent on particlesize and chemical form [9] It has been reported as an agentwhich may indirectly activate other carcinogens responsibleto generate tumors into key organs of the body such as lungsskin liver bladder and kidney [10ndash14] After absorptioninorganic arsenic rapidly binds to hemoglobin in erythro-cytes Blood arsenic is redistributed quickly (within 24 h) tothe liver kidneys heart and lungs and to a lesser degree tothe nervous system GI tract and spleen Arsenic undergoeshepatic biomethylation to form monomethylarsonic anddimethylarsinic acids that have relatively lower toxicity [15]

21 Arsenic Mediated Modulation of Transcription FactorsArsenic has been found to modulate the functions oftranscription factors (as nuclear factor kappa-light chainenhancer of activated B-cells (NF-120581B) activator protein 1(AP-1) and tumor suppression protein (p53)) NF-120581B AP-1 and p53 bind certain consensus sequences of DNA andregulate the cellular responses As reviewed by Valko et al[3] the heavy metals exhibit differential impacts on the threemajor mitogen activated pathway (MAP) kinases (such asextracellular signal regulated protein kinases ERKs c-JunN-terminal kinase JNK and stress activated protein kinaseknown as SAPK or MAPK or p38) For example arsenic hasbeen shown to induce ERKs and JNKs in JB6 cells the formermay promote carcinogenesis while the latter may promoteapoptosis [16 17] Further it was demonstrated that the effectsof arsenic mediated through MAPK pathways and PKC maycause induction of AP-1 a transcriptional factor involved intumour promotion [18ndash20] The negative impact of arsenicon the TNF120572-induced NF-120581B activation via inhibition ofthe IkB an inhibitory protein of NF-120581B kinase complexhas been demonstrated [3 21 22] Very recently Sun et al[23] have shown that carcinogenic metalloid arsenic inducesexpression of mdig (mineral dust-induced gene) oncogenethrough JNK and STAT3 (signal transducer and activator oftranscription 3) activationThe regulation of transcription byarsenic and its biological effects are summarised in Figure 2

22 Oxidative Stress Induced by Arsenic The oxidative stressis caused due to an imbalance between the production offree radical species and antioxidant defense system of anorganism that is the ability of any biological system to readilydetoxify the reactive oxygen intermediates or easily repair theresulting damage

One source of reactive oxygen under normal condi-tions in humans is the leakage of activated oxygen frommitochondria during oxidative phosphorylation HoweverE coli mutants that lack an active electron transport chainproduced as much hydrogen peroxide as wild-type cellsindicating that other enzymes contribute to the bulk ofoxidants in these organisms One possibility is that multiple

Diffusion

Activation of signal transduction pathway

Anion transporterPlasma membrane

Transcriptional regulation

Biochemicalphysiological effects

MEKK 3 4MEKK 2 3 4

As5+

As5+

As3+

As3+

(JNK MAP4K MAP3K)

Figure 2 Effect of activation by arsenate (As(V)) and arsenite(As(III)) on the signal transduction pathways As(V) and As(III)activate different proteins to regulate c-Jun N-terminal kinase(JNK) which functions in the stress-activated protein kinase path-way (SAPK) A SAPK pathway is a sequential protein kinase cascadewheremitogen-activated protein (MAP) kinase kinase kinase kinase(MAP4K) phosphorylates and activates a MAP kinase kinasekinsase (MAP3K) which repeats the cycle by phosphorylating andactivating the next kinase in the cascade The small GTP bindingproteins (G-proteins Ras Rac Cdc-42 and Rho) are localizedupstream of the sequential protein kinase cascade The aniontransport protein regulates entry of arsenate into the cell whilearsenite which is an uncharged arsenic species enters the cell bydiffusion The small G-proteins that are regulated by As(V) andAs(III) do not appear to play a significant role in As(V) and As(III)signaling to JNK The p-21-activated kinase (PAK) plays a role inAs(III)-dependent JNK activity MEKK3 and MEKK4 are involvedin both As(V) and As(III) activation of JNK while MEKK2 may beinvolved in the activation of JNK by As(III) (Porter et al) [6]

redox-active flavoproteins all contribute a small portion tothe overall production of oxidants under normal conditionsOther enzymes capable of producing superoxide are xanthineoxidaseNADPHoxidases and cytochromes P450Hydrogenperoxide (H

2O2) is produced by a wide variety of enzymes

including several oxidases ROS play important roles in cellsignalling a process termed as redox signaling The beststudied cellular antioxidants are the enzymes superoxide dis-mutase (SOD) catalase and glutathione peroxidase (GPx)Fewwell studied antioxidants include the peroxiredoxins andthe recently discovered sulfiredoxinOther enzymes that haveantioxidant properties (though this is not their primary role)include paraoxonase glutathione-S transferases (GST) andaldehyde dehydrogenases (ADH)

Arsenic is known to produce ROS and hence to generateoxidative stress [24] One of such studies conducted in humanpopulations exposed to varying concentrations of arsenicindicated that this metal caused disruption of cell signalingpathways via ROS generation The arsenic induced O

2∙

minus wasfound to be playing crucial role in this process as a chiefparticipating species It was later on transformed to the morereactive oxygenated species such asH

2O2and ∙OHThe inter-

action of these species with biological macromolecules mayfurther lead to DNA damage and its hypo- or hypermethy-lation in addition to lipid peroxidation (LPO) and alterationsin regulatorymechanisms of cell proliferation and deathThis


study indicated that arsenic induced oxidative stress resultsin alterations in the levels of some antioxidant enzymes suchas superoxide dismutase (SOD) catalase (CAT) glutathioneperoxidase (GPx) and heme oxygenase-1 (HO-1) as well asthe nonenzymatic factors such as sulfhydryl group containingpeptides and proteins in human systems which could beassociated with toxicity of arsenic [24]

The oxidative stress has been recognized as a majorcomponent in the chain of pathogenic events that causelate complications in diabetes mellitus [25] Several otherworkers have opined that it may also be considered as amajorcontributor to vascular and neurological complications inpatients with diabetes mellitus [26ndash31] The involvement ofoxidative stress in the cytotoxicity and genotoxicity of arsenic[32] has been reported It could be due to generation ofNO causing DNA damage and activating poly (ADP-ribose)polymerase (PARP) [32] a major cause of islet cell damage indiabetes [33]

The lipid peroxidation (LPO) has been found to besignificantly increased in arsenic treated animals as com-pared to control thus corroborating well with the earlierspeculations that arsenite induces oxygen free radical orpromotes formation of lipid peroxides [34] High levels ofsuch lipid peroxidation products have been indicated inthe development of diabetes [35ndash37] This finding reflectsthe possibility that the chronic oral arsenic exposure maycause significant damage to the pancreas particularly tothe endocrine cellular components of pancreatic islets Ittherefore may be responsible for transforming the normalphysiological features of the oral glucose tolerance test to adiabetic form In 2002 Tibbetts has shown that exposure toarsenic causes oxidative stress that damages cellular healthand triggers onset of many diseases [38]

In addition monomethyl arsenous compounds producedwhen arsenic covalently binds to the reactive thiols ofendothelial NO synthetase (NOS) result in inactivationof enzyme activity [39] A correlation among the arsenicinduced ROS generation interaction with NOS and influ-ence on cell signaling cascade throughmitogen activated pro-tein kinases (MAPKs) and other factors leading to apoptosisand cytotoxicity have been demonstrated by Flora et al [5]

Glutathione (GSH) acts as a natural antioxidant andpotential reducing agent and is reported to protect the bodysystems as a cellular protagonist from damaging effects ofoxidative stress (OS) [40 41] It is an intracellular tripeptideknown as nonprotein thiol consisting of three amino acidssuch as glutamic acid cysteine and glycine and is chemicallyrecognized as 120574-l-glutamyl-l-cysteinyl-glycine It containsan unusual peptide linkage between the amine group ofcysteine and the carboxyl group of the glutamate side chainThe thiol groups are kept in a reduced state at a concentrationof approximately sim5mM in animal liver cells In healthy cellsand tissue more than 90 of the total glutathione pool isin the reduced form (GSH) and less than 10 exists in thedisulfide form (GSSG) In effect GSH is capable of reducingany disulfide bond formed within cytoplasmic proteins tocysteines by serving as an electron donor In fact in thereduced state the thiol group of cysteine is able to donate areducing equivalent (H+ + eminus) to other unstable molecules

such as ROS In this process GSH is converted to its oxidizedform glutathione disulfide (GSSG) GSH is found almostexclusively in its reduced form since the enzyme that revertsit from its oxidized form glutathione reductase (GRx) isconstitutively active and inducible upon oxidative stressTherefore the decreased ratio of reduced glutathione (GSH)to oxidized glutathione (GSSG) within cells is often usedscientifically as a measure of cellular toxicity or an indicativeof OS generation in the cells or tissues [3 41]

The arsenic exposure is reported to cause depletion ofGSH in several biological systems [42ndash45] Some importantchemical events such as high affinity of As (III) to GSH capa-bility of GSH to reduce As (V) into As (III) and conversionof GSH to ROS generation by arsenic collectively contributeto oxidation of GSH into GSSG thereby reducing its netconcentration in the cell The network of biochemical reac-tions having influence on arsenic cellular reduction systemsROS production lipid peroxidation (LPO) and levels of GSH(through involvement of vitamins C and E) including impacton the activities of antioxidant enzymes (such as glutathionereductase (GPx) superoxide dismutase (SOD) andGRx) areshown by other workers [3 42] Using the TRL 1215 cell line(a rat epithelial liver cell line originally derived from the liverof 10-day-old Fisher F344 rats) Santra et al [45] have shownthat the methylated form of arsenic (dimethylarsinic acidDMA) is a complete carcinogen in rodents They found thatarsenite was very cytotoxic in these cells (LC

50= 35 120583M after

48 h of exposure) With arsenite exposure most dead cellsshowed histological and biochemical evidence of necrosisArsenite cytotoxicity increased markedly when cellular GSHwas depleted [45] It was found that the trivalent methylatedand relatively less ionizable arsenic metabolites might beunusually capable of interacting with cellular targets such asproteins and even DNA [46]Their findings indicated arsenicinduced OS as a possible mode of action for carcinogenesisArsenic can affect the central nervous system (CNS) throughseveral pathways and hence induce significant alterations inthe behavioural pattern of experimental animals Arsenicenters the CNS accumulates and undergoes biomethylationin the brain The neurotoxicity of arsenicals observed couldbe attributed to the adverse effects of the parent compoundor to the effects of the methylated metabolites on antioxidantenzymes and neurotransmitter metabolism [3]

3 Clinical and PathophysiologicalAspects of Arsenic Toxicity

31 Toxicity A small amount of inorganic arsenic is excretedunchanged as it has been observed that about 50 of ingestedarsenic can be eliminated in the urine in 3 to 5 days withresidual amounts remaining in the keratin-rich tissues suchas nails hair and skin Depending on its oxidative statesarsenic poisons cells by one of two key mechanisms (1) bybinding the sulfhydryl groups on critical enzymes and (2)through depletion of lipoate by trivalent arsenite Lipoate isinvolved in the synthesis of key intermediates in the Krebscycle Hence the depletion of lipoate results in inhibitionof the Krebs cycle and oxidative phosphorylation leading


to ATP depletion Pentavalent arsenate on the other handcan replace the stable phosphate ester bond in ATP with thearsenate ester bond thereby rapidly hydrolyzing (arsenolysis)uncoupling oxidative phosphorylation and depleting ATPstores The combination of inhibiting cellular respirationand uncoupling oxidative phosphorylation results in cellularenergy depletion resulting in cell death in high-energydependent tissues [47]

32 Clinical Features Acute arsenic poisoning may producedisturbance in gastrointestinal (GI) tract involving nauseavomiting abdominal pain and bloody rice water diarrheaHypovolemic shock may follow in severe cases as a result ofendothelial damage and third spacing of fluid Hematologicabnormalities (bone marrow depression pancytopenia ane-mia and basophilic stippling) usually appear within 4 days oflarge ingestions QT interval (a measure of the time betweenthe start of the Qwave and the end of the Twave in the heartrsquoselectrical cycle) prolongation and ventricular arrhythmiassuch as torsade de pointes (a French term that literallymeans ldquotwisting of the pointsrdquo) can occur several days afterinitial improvement in GI symptoms Arsenic poisoningmaycause distal symmetric peripheral neuropathy with burningand numbness in the hands and feet and a syndrome ofrapidly developing ascending weakness similar to Guillain-Barre (Guillain-Barre syndrome is a disorder in which thebodyrsquos immune system attacks part of the peripheral nervoussystem) Alongwith the peripheral nervous system CNSmayalso be affected with the development of encephalopathy

The chronic arsenic exposure results into dermatologicchanges (hyperpigmentation and keratosis on the palms andsoles) nails may exhibit transverse white bands known asMees lines (the result of interruption of the nail matrix) andare not specific to arsenic Cardiovascular effects include anincreased incidence of hypertension and peripheral vasculardisease Sporadic outbreaks of peripheral vascular gangreneknown as blackfoot disease have occurred in Taiwan due tohigh levels of arsenic in the drinking water Chronic arsenicexposure has been associated with various malignanciesincluding skin lung liver bladder and kidney Inorganicarsenic crosses the placenta and may be teratogenic inanimals

33 Diagnosis of Arsenic Toxicity Some arsenic compoundsare radiopaque and visible on abdominal radiograph Anelectrocardiogram is indicated to assess the QT intervalwhich may be prolonged Nerve conduction testing typicallyshows evidence of distal symmetric sensorimotor axonopa-thy The most important and reliable diagnostic test is aquantitative 24 h urinary arsenic excretionNormal values areless than 50mgLThe seafood ingestion however may causesignificantly elevated urinary arsenic values and speciationof the urinary arsenic can be performed to differentiateinorganic from organic forms Although blood arsenic maybe elevated initially in the acute poisoning levels rapidlydecline in the next 24 to 48 h despite continued symptomsand increased urinary arsenic excretionWhole blood arseniclevel is usually less than 1mgdL Residual arsenic in hair and

nailsmay persist for prolonged periods but external contami-nationmay render interpretation difficult and unreliable [47]

34 Management of Toxicity of Arsenic Treatment of arsenicpoisoning begins with the removal from the exposure sourceSupportive measures and chelation therapy are the main-stays of management Volume resuscitation is of paramountimportance in the severely poisoned patient and chelationwith dimercaprol or succimer (23-dimercaptosuccinic acidDMSA) should be considered in patients who have symptomsor increased body burden of arsenic Hemodialysis may beconsidered for patients who have renal failure HoweverusingA375 cells the role of arginine a component of aqueousgarlic extract has been shown in remediation of sodiumarsenite induced toxicity [48] In addition coadministrationof folic acid and vitamin B12 has been shown to preventcardiac tissues from arsenic induced oxidative damage invivo [49]

4 Lead

Lead (Pb Latin plumbum atomic number 82) is anotherubiquitous toxic metal detectable practically in all phases ofthe inert environment and biological systems [50ndash52] Lead isfrequently used in the production of batteries metal products(solder and pipes) ammunition and devices to shield X-raysleading to its exposure to the people working in these indus-tries Use of lead in gasoline paints and ceramic productscaulking and pipe solder has been dramatically reduced inrecent years because of health concerns Ingestion of contam-inated food and drinking water is the most common sourceof lead exposure in humans Exposure can also occur viainadvertent ingestion of contaminated soildust or lead-basedpaint The most susceptible population to lead poisoning ischildren particularly soldiers infants in neonatal periodsand the fetus [53ndash56] Several reviews and multiauthoredbooks on toxicology on lead are available [57ndash61] It getsinto water from the corrosion of plumbing materials Leadpoisoning (also known as saturnism plumbism Devon colicor painterrsquos colic) is a medical condition caused by increasedlevels of lead in the blood [62]

The Centers for Disease Control and Prevention (CDC)and others state that a blood lead level (BLL) of 10 120583gdLor above is a cause for concern [63 64] However leadcan impair development of animals even at BLLs below10 120583gdL [65 66] According to the World Health Organiza-tion (WHO) [67] and United Nations Food and AgricultureOrganization (UNFAO) Joint Expert Committee on FoodAdditives (JECFA) [68] the provisional tolerable weeklyintake (PTWI) for Pb should not exceed 25mg kgminus1dminus1 Afterexceeding this safe concentration limit lead can induce abroad range of physiological biochemical and behavioraldysfunctions in humans and laboratory animals includingperipheral and CNS haemopoietic system cardiovascularsystem kidney liver and reproductory systems of malesand females [3 69] However some workers have reportedthat lead at even low concentration may cause behaviouralabnormality impairment in hearing learning and cognitive


functions in humans and experimental animals [69 70] Ithas been shown to cause permanently reduced cognitivecapacity (intelligence) in children with apparently no lowerthreshold to the dose-response relationship (unlike otherheavy metals such as mercury) [71] This neurotoxicity waslater found to be associated with lead-induced production ofROS which caused increase or decrease in the levels of lipidperoxidation or antioxidant defense mechanisms in the brainof experimental animals and the effects were concentrationdependent [72ndash74]

Since lead has no known physiologically relevant role inthe body its toxicity comes from its ability to mimic otherbiologically important metals most notably calcium ironand zinc which act as cofactors in many enzymatic reactionsLead is able to bind to and interact with many of the sameenzymes as these metals but due to its differing chemistrydoes not properly function as a cofactor thus interferingwith the enzymersquos ability to catalyze its normal reaction(s)Moreover lead is now known to induce production of ROSand RNS and hence this heavy metal exhibits ability togenerate oxidative stress in the body of those occupationallyexposed to lead and experimental animalmodels treatedwithvarying concentrations of lead [72ndash75]

41 Mechanisms of Lead-Induced Oxidative Stress Themech-anisms of lead-induced oxidative stress primarily includedamage to cell membrane and DNA as well as the enzy-matic (catalase SOD GPx and glucose-6-phosphate dehy-drogenase (G6PD)) and pool of nonenzymatic antioxidantmolecules such as thiols including GSH of animals andhuman systems [3 5]

42 Lead-Induced Membrane Damage It is known that thepolyunsaturated fatty acids constituting the cellular mem-brane are highly prone to react with ROS and get peroxidizedin completely different chemical entities which perturbsvaried key functions of the cell membrane such as membranepermeability and receptors activities of membrane boundenzymestransmembrane proteins [76 77] ion channelsand transport of ions and exo- and endocytosis as wellas signal transduction Some in vitro and in vivo animalstudies have indicated that lead-induced oxidative damagesignificantly contributes to enhancement of erythrocytesmembrane fragility during lead intoxication [78 79]

43 Lead-Induced Perturbations in Hematological IndicesLead has multiple hematological effects In lead-inducedanemia the red blood cells are microcytic and hypochromicas in iron deficiency there are an increased number ofreticulocytes with basophilic stippling The anemia resultsfrom two basic defects (1) shortened erythrocyte life spanand (2) impairment of heme synthesis Shortened life span ofthe red blood cells is due to the increasedmechanical fragilityof the cell membrane The biochemical basis for this effect isnot known but the effect may be accompanied by inhibitionin the activity of sodium and potassium dependent ATPases[79 80] Lead is shown to induce changes in the composition

of red blood cell (RBC) membrane proteins and lipids and toinhibit hemoglobin synthesis [3 81]

In the heme biosynthesis pathway there are fourmajor key enzymes that are the targets of toxic effects byheavy metal These enzymes are ALA dehydratase (ALADalso known as porphobilinogen synthase cytosolic innature) uroporphyrinogen decarboxylase (UROD cytosolicin nature) protoporphyrinogen oxidase (PPOmitochondrialin nature) and ferrochelatase (FeC mitochondrial enzyme)Among these ALAD which catalyses the conversion oftwo molecules of 120575-aminolevulinic acid (ALA which issynthesized into mitochondria and released into cytoplasm)into one molecule of porphobilinogen (PBG) at the secondstep of heme biosynthesis pathway represents one of themost sensitive sites of inhibition of heme biosynthesis by lead(Pb2+) though several other heavy metals including arsenic(III) cadmium (Cd2+) mercury (Hg2+) silver (Ag2+) andcopper (Cu2+) also influence its activity [82 83]Thesemetalsbind to the thiol groups of allosteric sites and according totheir structure provoke allosteric transitions to the activeor inactive form of the enzyme The lead poisoning causesan increase in ALA in the circulation in the absence of anincrease in porphobilinogen The accumulation of ALA hasbeen shown to be involved in lead-induced oxidative damageby causing formation of ROS The ALAD is a cytosolicenzyme containing thiol (SH) groups and requires Zn for itsoptimal activity Since Pb exhibits binding affinity to thiolgroups hence it has ability to inhibit activitiesfunctionsof all those enzymesproteins including ALAD possessingsulfhydryl groups accessible to this metal ion Like ALADFeC which is responsible for catalyzing the joining of proto-porphyrin IX and Fe2+ finally to form heme is also vulnerableto inhibition by lead and mercury [84 85] Disruption ofFeC activity leads to an accumulation of Zn-protoporphyrinin erythrocytes which serves as the major biomarker and adiagnostic tool in detecting childhood lead poisoning

44 Influence of Lead on DivalentMetalsWorking as Cofactorsand Their Binding Sites The mechanisms of toxicity of leadchiefly (1) involve substitution of Ca2+ by lead therebyaffecting all those physiologicalbiochemical processes ofthe cell which requires calcium and (2) cause neurotoxicityLead can cross the cell membrane in various ways whichare not yet entirely understood Lead transport through theerythrocyte membrane is mediated by the anion exchangerin one direction and by the Ca-ATPase pump in the otherIn other tissues lead permeates the cell membrane throughvoltage-dependent or other types of calcium channels Afterreaching the cytoplasm lead continues its destructive mim-icking action by occupying the calcium binding sites onnumerous calcium-dependent proteins Lead has high affin-ity for calcium-binding sites in the proteins picomolarconcentration of lead can replace calcium in micromolarconcentrations Lead binds to calmodulin a protein whichin the synaptic terminal acts as a sensor of free calciumconcentration and as a mediator of neurotransmitter releaseThe chemical basis for lead mimicking calcium is not clear


Calcium and lead radically differ in their electronic struc-tures and ionic radii Calcium lacks coordination chemistrywhereas lead has a broader coordination complex formationproperty Calcium prefers oxygen ligands whereas lead mayalso complex with other ligands such as OHminus Clminus NO

3

minus andCO3

2minus especially the sulfhydryl group Furthermore it altersthe functioning of the enzyme protein kinase C a virtuallyubiquitous protein which is of crucial importance in numer-ous physiological functions Kinase C is normally activatedbymodulators outside the cell (hormones neurotransmittersetc) through an enzyme chain and in a calcium-dependentmanner Besides many other functions the activated kinasedirectly affects the expression of the immediate early responsegenes (IERG)

45 Neurotoxicity of Lead Lead as a systemic toxicant isa neurotoxin that has been linked to visual deteriorationcentral and peripheral nervous system disorders [86] renaldysfunction [87] and hypertensive cardiovascular disease[88] Khalil-Manesh et al [88] have presented the interplay ofreactive oxygen species and nitric oxide in the pathogenesisof experimental lead-induced hypertension pointing outtowards the role of oxidative stress (OS) as a major mediatorin this disease Lead affects virtually every organ system ingeneral and the central nervous system (CNS) of developingbrain in particular The children therefore are more prone tothe risk of lead toxicity than adults

46 Lead Exposure and Blood Brain Barrier Lead has abilityto cross the blood-brain barrier (BBB) and to substitute forcalcium ions It interferes with the regulatory action of cal-cium on brain cells functions and disrupts many intracellularbiological activities Lead-induced damage in the prefrontalcerebral cortex hippocampus and cerebellum regions canlead to a variety of neurologic disorders [89] Experimen-tal studies have shown that Pb-induced neurotoxic effectscould potentially be mediated through alterations in theinteractions of glucocorticoids with the mesocorticolimbicdopamine system of the brain [90] Many of the neurotoxiceffects of lead appear related to the ability of lead to mimic orin some cases inhibit the action of calcium as a regulator ofcell function as discussed above At a neuronal level exposureto lead alters the release of neurotransmitter frompresynapticnerve endings Spontaneous release of neurotransmitter isenhanced probably due to activation of protein kinases inthe nerve endings On the other hand its evoked release isinhibited possibly due to the blockade of voltage-dependentcalcium channels This disruption of neuronal activity maylead to alterations in the developmental processes of synapseformation resulting into a less efficient brain with cognitivedeficits

Brain homeostaticmechanisms are disrupted by exposureto higher levels of lead The final pathway appears to be abreakdown in BBB Lead-induced mimic or mobilization ofcalcium and activation of protein kinases may alter the func-tion of endothelial cells in immature brain and disrupt BBBIn addition to a direct toxic effect upon the endothelial cellslead may alter indirectly the microvasculature by damaging

the astrocytes that provide signals for the maintenance ofintegrity of BBB [91] Lead uptake through BBB into the brainproceeds at an appreciable rate consistent with its action as apotent central neurotoxin [92]

The BBB is a system of tightly joined endothelial cells thatform a transport barrier for certain substances between thecerebral capillaries and the brain tissue Under these condi-tions solutes may gain access to brain interstitium via onlyone of two pathways (i) lipid-mediated transport (restrictedto small molecules with a molecular weight lt700Da andgenerally proportional to the lipid solubility of the molecule)or (ii) catalyzed transport (carrier-mediated or receptor-mediated transport) processes The transport mechanism isnot totally understood but it most likely involves passiveuptake of PbOH+ ions In the brain lead accumulates inastroglia cells which function as a lead sink protecting themore vulnerable neurons Astroglia cells (or astrocytes orneuroglia) are the nonneuronal cells of the nervous systemThey not only provide physical support but also respond toinjury regulate the ionic and chemical composition of theextracellular milieu participate in the BBB and blood-retinabarriers (BRB) form the myelin insulation of nervous path-ways guide neuronal migration during development andexchangemetabolites with neurons Astrocytes are the largestand most numerous neuroglial cells in the brain and spinalcord They have high-affinity transmitter uptake systems andvoltage-dependent and transmitter-gated ion channels andcan release transmitter but their role in signalling is not wellunderstood On the other hand astrocytes may be vulnerableto the toxic effects of Pb2+ Both in astroglia cells and inneurons lead uptake is mediated by calcium channels

47 Lead Adversely Influences Neurotransmission SystemsThe effects of lead on the brain including mental retardationand cognitive deficit are mediated by its interference withthree major neurotransmission systems (1) the dopaminer-gic (2) cholinergic and (3) glutamatergic systemsThe effectsof lead on the first two systems are well established but theirmechanisms have not yet been described exhaustively Leadis known to directly interfere with the action of glutamatethe brainrsquos essential excitatory neurotransmitter at morethan half of the synapses in the brain and is critical forlearning The glutamate receptor thought to be associatedwith neuronal development and synaptic plasticity is theN-methyl-D-aspartate (NMDA) type receptor (NMDAR) Itserves as a direct target for lead and is blocked selectivelyby leadThis disrupts long-term potentiation which compro-mises the permanent retention of newly learned informationGlutamate binds to membrane receptors of different typesMicromolar concentration of lead can block the ion fluxthrough the membrane channel associated with NMDARwhich is also associated with neural network creation andmemory and learning functions In fact the adverse impactof lead on NMDAR has been shown to alter calcium sig-nalling pathways which are involved in learning andmemoryThe NMDAR-mediated calcium signaling can activate pro-tein kinase A (PKA) the mitogen-activated protein kinase(MAPK) and the calcium-calmodulin-dependent protein


kinase II (CAMKII) pathways [5 93] These pathways finallyactivate c-AMP response element binding protein (CREB)a transcription factor which regulates the transcription ofgenes in nucleus essential for learning and memory [5 94]

Lead also targets the activity of Ca2+-dependent proteinkinase C (PKC) by competing with calcium binding sites andcauses neurotoxicity PKC is a critical enzyme involved inmany cell signaling pathways In neuronal cells of developingrat brain Pb has been shown to adversely influence theactivity of an enzyme nitric oxide (NO) synthase (nNOS)responsible for catalysis of NO synthesis which could beconsidered as another mechanism of neurotoxicity caused bylead The activation of NMDAR is associated with triggeringsynthesis of NO utilizing nNOS as a biocatalyst Since leadinterferes in functioning of NMDAR via competing withcalcium it is quite likely that lead would be also inhibitingnNOS activity and hence the biosynthesis of NO as wasobserved in hippocampus of Pb2+- exposed rats [5]

Recently the investigation on effects of prenatal andpostnatal lead exposure on monoamine oxidase (MAO)activity in the different stages of rat brain development hasindicated increasedMAOactivity inmost of the brain regionsespecially at early developmental stages (2 weeks of age) andthe toxicity was gradually decreased with the development ofrats It has been postulated that the increased MAO activityby lead intoxication may contribute to the neurobehavioralchanges such as cognitive and attention deficit as well ashyperactivity [5 90] Similar results showing lead-inducedneurotoxicity were obtained with the mitochondrial MAOwhen investigated in different parts of the brain of leadexposed rats of varying age groupsThe activity of another keyenzyme acetylcholinesterase (AChE) responsible for smoothfunction of nerve impulse transmission has been shown tobe highly sensitive towards lead exposure in different partsof developing rat brain as well as in the erythrocytes ofhumans occupationally exposed to lead [5 90] Anotherstudy observing the perinatal effects of lead exposure onthe monoaminergic GABAergic and glutamatergic systemsin the striatum cerebral cortex (Cx) dorsal hippocampus(d-Hipp) and basal-medial hypothalamus or rat brain hasindicated regional alterations in monoamine contents withincrease in dopamine and serotonin or their metabolitesThe glutamate levels decreased in all brain regions studiedwhile gamma-aminobutyric acid (GABA) content decreasedonly in the Cx [90] showing depletion of neurotransmittersdue to lead exposure which may be associated with possi-ble neurobehavioral impairment However a separate studyobserving the effect of lead in pregnant rats concludes thatmaternal Pb2+ treatment distorts the dopaminergic-nitrergicinteraction in the nigrostriatal pathway without involvingROS production in this process [95]

Another target for lead attack could be a thiol groupcontaining key enzyme of pentose phosphate pathway thatis G6PD which catalyses conversion of glucose 6-phosphateinto 6-phosphoglucono-120575-lactone by oxidation (a rate lim-iting step in pentose phosphate pathway) and generatesNADPH NADPH as a reducing energy is required tomaintain optimum levels of glutathione (GSH) in the cellular

systems via reduction of glutathione disulfide (GSSG) toGSH by glutathione reductase (GR) Of greater quantitativeimportance is the production of NADPH for tissues activelyengaged in biosynthesis of fatty acids andor isoprenoidssuch as the liver mammary glands adipose tissue and theadrenal glands G6PD is activated by its substrate glucose-6-phosphateThe usual ratio of NADPHNADP+ in the cytosolof tissues engaged in biosynthesis is about 1001 Increasedutilization ofNADPH for fatty acid biosynthesismay increasethe level of NADP+ and stimulate the activity of G6PD toproduce more NADPH NADPH is utilized by mitochondriaas well as RBCs which is deficient in containing mitochon-dria NADPH maintains the level of glutathione in RBCsthat helps protect them against oxidative damage Thus theinhibition of G6PD by lead may exert a serious bearing ontothe RBCs However inhibition of phosphoribosyltransferasesby lead has also been suggested to be a potential mechanismof lead toxicity in RBCs [77]The studies on another cytolosicNADPH utilising enzyme from ratrsquos kidneys thioredoxinreductase-1 which is a selenoprotein involved in catalysis ofreduction of oxidised thioredoxin utilising NADPH as anelectron donor have shown it to be strongly inhibited dueto both the acute and chronic exposure of lead The effectwas mediated via oxidative stress as this metal ion alteredsignificantly the levels of known markers of lead-inducedoxidative damage for example the activities of antioxidantenzymes delta aminolevulinate dehydratase glutathione S-transferase nonprotein thiol groups lipid peroxidation andantioxidant enzymes in the kidney [96ndash100]

Glutathionylation has been studied in the context ofoxidative stress and from this perspective it is one ofthe many forms of oxidation of thiols of protein cys-teines Mechanisms of glutathionylation include (1) ROS-dependent glutathionylation via sulfenic acid (2) ROS-dependent glutathionylation via SHSS exchange reaction (3)ROS-dependent glutathionylation via radical reactions and(4) ROS-independent glutathionylation [97 98] However agroup of enzymeplayers are involved in protein thiol oxidore-duction called protein disulfide oxidoreductases (PDOR)[98] as shown in Table 2 that are equipped with abilities tobring back the oxidizedinactivated thiol group containingproteins back to normal and active state These enzymesoften contain a CXXC redox active dithiol motif and catalyzethiol-disulfide exchange reactions with different substratespecificities In particular Trx and Grx systems are generallydescribed as protein disulfide reductants and are assignedan ldquoantioxidantrdquo function [99ndash101] More recently Srx amonothiol enzyme was shown to reduce glutathionylatedproteinsThe protein disulfide isomerases (PDIs) are thoughtto play a major role in the formation of disulfide bondsfor instance during protein folding in the endoplasmicreticulum [102]

48 DNA Damage and Altered Calcium Homeostasis Theresults of some studies as compiled by Krejpcio and Wojciak[103] and Florea and Busselberg [65] have shown that leaddepletes glutathione and protein bound sulfhydryl groupswhich induce excess formation of GSH from cysteine via


Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview

Physicalchemicalclin

ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand

pentavalentsaltsgt90organic

also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon

ductorsherbicidesand

pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes

skintetraethylleadin

gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and

urinarylevels(acute)hairor

fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40

ugdLurinaryleadgt80120583gdL

Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s

Acute-damagetomucosa

sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest

painsnauseadizziness

diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis

tachycardiagoiterincreasedurinaryHg

Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)

chronicpenicillaminew

odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure

chelationtherapywith

CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim

ethylcysteine(penicillamine)

mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk

gminus1 dayminus1(EPA

reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


120574-glutamyl cycle (a metabolic cycle for transporting aminoacids into cells) in addition to ROS production HoweverGSH may not be efficiently supplied if depletion continuesbecause of chronic exposure of lead

5 Clinical and PathophysiologicalAspects of Lead Toxicity

51 Pediatric Toxicity The young children (up to 2 yearsof age) use hand-to-mouth activity to explore their envi-ronment Children who play with objects containing leadadded paints or live in an environment that is contaminatedwith lead are more likely to suffer from the effects of leadpoisoning such as central neurotoxicity At lower levels (1ndash50mgdL) lead may cause subtle cognitive and behavioralchanges difficult to differentiate from normal developmentalvariance whereas at moderate levels (50ndash70mgdL) childrenmay display a global decrease in activity such as childrenwho do not enjoy playing or who developmentally fallbehind their peers These symptoms have been classifiedas preencephalopathic symptoms and are most prominentbetween 1 year and 5 years of age With severe lead toxicity(gt70mgdL) children may be encephalopathic with comaseizures altered mental status and symptoms consistentwith increased intracranial pressure Encephalopathy fromlead occurs most commonly between the ages of 15 and 30months Other symptoms of childhood lead toxicity includeanemia peripheralmotor neuropathy GI complaints such asanorexia vomiting and abdominal pain and growth delayLead readily crosses the placenta and has been reported tocause fetal toxicity The primary route of lead exposure inchildren is through the GI tract Lead is probably taken upat calcium absorption sites which have increased activityat times of rapid growth The central neurotoxicity causedby lead is caused by disruption of the intercellular junctionthat seals the capillary endothelium The mechanism of thisdisruption is interference with cellular calcium metabolismand second messenger signaling systems With the loss ofits tight seal the BBB is less effective and the capillariesleak resulting in an increase in intracranial fluid and aresultant increase in intracranial pressure This effect oflead is more prominent in young children because of theirimmature BBB before the exposure Chronic exposure tolead affects numerous neurotransmitter systems increasingthe spontaneous release of dopamine acetylcholine andGABA blocking N-protein kinase C These effects resultin an increase in random synaptic signals termed synapticnoise and a decrease in ability of neuron to produce asynaptic signal in response to a true stimulus A human hasthe most neurologic synapses at the age of 2 after whichthe body through apoptosis rapidly starts to prune faultyand unnecessary synapses The determination of whethera synapse is kept or destroyed is related to feedback fromneurotransmitters and neurotransmitter receptors Becauselead interferes with neurotransmitters and their receptorsit results in a disruption of synapse formation and synapsedestruction

Lead has two main toxic effects on the hematologicsystem reduction of erythrocyte lifespan and decreasedhemoglobin biosynthesis Lead causes inhibition ofpyrimidine-51015840-nucleotidase and inhibition of Na-K-ATPase leading to decreased energy use by the erythrocyteand a decrease in cell membrane stability Pyrimidine-51015840-nucleotidase is necessary for the removal of degradedRNA and its inhibition by lead causes erythrocytes toform clumps giving the cells the classic basophilic stipplingappearance Lead interferes with several enzymes in theheme synthesis pathway including aminolevulinic acidsynthetase d-aminolevulinic acid dehydratase (ALA-D)ferrochelatase and coproporphyrinogen decarboxylaseALA-D in particular can be inhibited by minimal leadexposure

52 Diagnosis Blood lead levels are the best indicator oflead exposure Venous blood samples are necessary becausecapillary samples can give false positives because of skincontamination All children who fit into a high-risk category(mainly based on socioeconomic factors) should be screenedwith a blood lead level at 1 year and 2 years of age A completeblood countmay showahypochromicmicrocytic anemia andstippling of the RBCs

53 Management The most effective treatment for leadtoxicity is removal of the patient from the lead-containingenvironment and cessation of exposure Pediatric patientswho present with symptoms of lead encephalopathy or withblood levels gt70mgdL should be considered candidatesfor parenteral chelation therapy with either dimercaprol orsuccimer and CaNa

2EDTA Chelation with oral succimer

should be considered in children who are asymptomatic withblood lead levels between 45 and 69mgdL

54 Adult Toxicity Most adult lead poisonings occur fromoccupational respiratory exposures Lead-induced hyper-tension is the most common symptom attributed to leadexposure in adults Patients can also develop anemia gastriccolic muscle and joint pain decreased fertility renal failureand peripheral motor neuropathy Rarely adults with bloodlead levels gt100mgdL present with encephalopathy Adultsmore commonly suffer from subtle neurologic deficits suchas fatigue and emotional lability after lead exposureThemainmechanism of lead-induced hypertension seems to be relatedto changes in vascular smooth muscle because of increasedactivity of the Na-Ca exchange pump and interference ofNa-K ATPase activity The progressive development of renalfailure may result after long-term environmental exposuresor the chronic release of deposited bone lead Lead disruptsmitochondrial phosphorylation and oxidation within thekidney leading to a decrease in energy-dependent transportThe end result of this disrupted transport is phosphaturiaglycosuria and aminoaciduria With chronic lead exposurethe kidneys are found to have lead-protein complex inclusionbodies which help in excretion of lead As chronic leadexposure progresses fewer of these inclusion bodies are seen


and the renal tubules begin to show signs of interstitialfibrosis

Peripheral neuropathy from lead exposure is caused bySchwann cell destruction followed by demyelination andaxonal atrophy Upper extremity motor neurons are moresusceptible to damage from lead than sensory or lowerextremity neurons resulting in the classic albeit rare andpresentation of bilateral wrist drop Leadrsquos total body burdenis stored mainly in bone with 70 of a childrsquos and 95 ofan adultrsquos total body burden stored in bone Within bonethere are two main storage areas the cortical bone which isa stagnant store and the trabecular bone which is a morebioavailable store Blood lead levels may increase duringtimes of increased bonemetabolismduring pregnancy osteo-porosis and fractures The half-life of lead in human bone isestimated to be up to 30 years

55 Diagnosis Thosewho display unexplained hypertensionencephalopathy peripheral motor neuropathy gastric colicand renal failure would be suffering from lead toxicityWork-ers with blood lead levels gt60mgdL or three consecutivelevels gt50mgdL should have a repeat level every monthThose with a level between 40 and 60mgdL should havea repeat level every 2 months and those with elevatedlevels lt40mgdL should have repeat levels every 6 monthsCurrently the best screening test is a venous blood lead levelA complete blood countmay show a hypochromicmicrocyticanemia and red blood cell stippling Urine analysis and basicmetabolic panel may be used to screen for renal toxicity TheX-ray fluorescence technology may be a useful screening testin the future to determine bone lead burden

56 Management The most effective therapy is limitationof exposure at work place by using personal protective gearimproving industrial engineering and adhering to safe workpractices Chelation usually is reserved for adults who aresymptomatic or who have a blood lead level gt70mgdLMildly symptomatic patients who have levels between 70 and100mgdL may require a course of oral succimer whereasthose patients who have encephalopathy or levelsgt100mgdLrequire intramuscular dimercaprol or oral succimer andintravenous CaNa

2EDTA A pregnant patient who has ele-

vated lead levels should be treated using the same standardsas a nonpregnant adult

6 Cadmium

Another transition metal cadmium (Cd) with atomic num-ber 48 is soft bluish-white chemically similar to the twoother metals in group 12 zinc andmercury It shows similari-ties with zinc and mercury in its preference of oxidation state+2 and lowmelting point respectively Cadmium is relativelythe most abundant and toxic element It was discovered in1817 by Friedrich Strohmeyer as an impurity in zinc carbon-ate (calamine) Being an important component of makingbatteries it is also used for cadmium pigments and coatingsand plating and as stabilizers for plastics Other applicationsinclude chemical stabilizers metal coatings alloys barrier to

control neutrons in nuclear fusion black and white televisionphosphors and blue and green phosphors for color televisionpicture tubes and semiconductors and in molecular biologyto block voltage-dependent calcium channels from fluxingcalcium ions

Cadmiumpoisoning is an occupational hazard associatedwith industrial processes such as metal plating and the pro-duction of nickel-cadmium batteries pigments plastics andother synthetics The main sources of exposure to cadmiumare specific professional atmospheres diet drinking waterand tobacco The primary route of exposure in industrialsettings is inhalation of cadmium-containing fumes whichcan result initially in metal fume fever but may progressto chemical pneumonitis pulmonary edema and deathCadmium possessing a long biological half-life (17ndash30 years)in humans accumulates primarily in liver and kidney [104]This long half-life of Cd is mainly due to its low ratio ofexcretion and its continued accumulation in the organismThe local agricultural communities in Japan consumingCd contaminated rice developed itai-itai disease and renalabnormalities including proteinuria and glucosuria It alsocauses osteoporosis anemia nonhypertrophic emphysemairreversible renal tubular injury eosinophilia anosmia andchronic rhinitis Cadmium is one of six substances banned bythe European Unionrsquos Restriction on Hazardous Substances(RoHS) directive because of its carcinogenic potential inhumans as it may cause cancers of lung prostrate pancreasand kidneyThe International Agency for Research onCancerof USA has classified Cd into the number 1 category ofcarcinogens [105]

The generation of ROS by Cd has been one of the knownmechanisms by which this heavy metal induces mutage-nesis [106] Due to increase in the levels of ROS variousphysiological perturbations develop for example increasedpermeability of BBB and alterations in synaptic transmissionFurther at cerebral level oxidative stress is associated withmany degenerative diseases such as amyotrophic lateral scle-rosis andAlzheimer ROS continuously generated during themetabolism of oxygen are transformed into highly reactivehydroxyl radicals attack the DNA cause breaks into strandsand even alter the bases It induces mutations and causes thesubsequent development of tumours [107 108] In differentcell systems the ability of Cd2+ to induce ROS generation hasbeen reported [109]

Cd2+ being a non-redox-active metal cannot initiate byitself the Fenton reactions [110] However it may generatenonradical hydrogen peroxide which may become a sourceof free radical via the Fenton reaction It therefore inducesoxidative stress through indirect processes Some of themechanisms through which Cd induces the formation ofROS include the following (1) decrease in the intracellu-lar GSH content (2) Cd combines with thiol groups ofenzymes involved in antioxidant mechanisms such as SODglutathione peroxidase (GPx) and catalase and inhibits theiractivities [111] (3) Cd forms cadmium-selenium complexes inthe active centre of GPx and inhibits the enzyme activity and(4) Cd inhibits complex III of the mitochondrial electronictransport chain and increases production of ROS [111] whichmay damage mitochondrial membrane and trigger onset of


apoptosis In addition changes in mitochondrial oxidativemetabolism may lead to energy deficit thereby affecting theessential cellular functions Thus Cd is capable of eliciting avariety of ROS (O

2∙ H2O2 and ∙OH) which could be the

main mechanism of cellular toxicity induced by this heavymetal Possibly Cd induced oxidative stress is involved in(1) causing DNA damagemutations [112] (2) oxidation ofproteins and (3) lipid peroxidation (LPO) which may causealterations in lipid composition of cellular membranes andfunctions In this context Lopez et al [113] have illustratedthat Cd induces LPO in cortical neurons due to increasedconcentration of ROS

Cd can replace iron and copper from a number ofcytoplasmic and membrane proteins like ferritin therebycausing rise in the concentration of iron and copper ionswhich may be associated with the production of oxidativestress via Fenton reaction [3 110] Another mechanism of Cdtoxicity may be carried out into the body by zinc bindingproteins that is the proteins with zinc finger motifs intoits structures Zinc and cadmium are in the same groupin the periodic table contain the same common oxidationstate (+2) and when ionized are almost the same in sizeDue to these similarities cadmium can replace zinc in manybiological systems particularly the systems that contain softerligands such as sulfur Cadmium can bind up to ten timesmore strongly than zinc in certain biological systems and isnotoriously difficult to remove In addition cadmium canreplacemagnesium and calcium in certain biological systemsalthough these replacements are rare [114 115]

Taking into account the effect of Cd on the centralnervous system (CNS) and endocrine system it is currentlyclassified as an endocrineneuroendocrine disruptor [116117] Cadmium induced significant increase in the levels ofmalondialdehyde (MDA) and glutathione peroxide (GSH-Px) has been reported by many workers in animal models[113]The genotoxic potential of cadmiumhas also been stud-ied in vivo into cadmium workers members of the generalpopulation and rodents Although not always consistentthese results suggest that cadmium is a clastogenic agent asjudged by the induction of DNA damage micronuclei sisterchromatid exchange (SCE) and chromosomal aberrations[112 113] Cadmium is also known to cause its deleteriouseffect by deactivating DNA repair activity [112] Studies haveshown that the number of cells withDNA single strand breaksand the levels of cellular DNA damage were significantlyhigher in cadmium-exposed animals [112 118 119]

Cadmium may be present as a cadmium-albumin com-plex in blood immediately after exposure [3] In this formthe liver may take up cadmium During first hour of intakecadmium in the liver will not be bound to metallothioneneCadmiummetallothionene complex to a large extent remainsin the liver but a small portion of it is released in theblood and another small portion is constantly turned overwhereby non-metallothionene bound cadmium is releasedout which all again induces new metallothionene and soon Cadmium metallothionene complex that occurs in theblood plasma is then quickly transported to the kidneywhere it is filtered through the glomeruli and reabsorbedby proximal tubule The metallothionene moiety is broken

down by the lysosomes and non-metallothionene boundcalcium is released in the tissue Such cadmium stimulatesrenal metallothionene synthesis and thus there is constantturnover of metallothionene Amajority of renal Cd is boundto metallothionene during long-term exposure situationHowever when the concentration of metallothionene boundCd exceeds a certain level at sensitive sites in the cell toxicityto renal tubules develops [120]

61 Cadmium Induced Apoptosis According to Kondoh etal [121] Cd induces apoptosis both in vitro and in vivoHowever the mode of action remains unclear They havereported that Cd induced apoptosis was partly dependenton mitochondria They further reported the involvement ofcaspase 9 which is the apex caspase in the mitochondria-dependent apoptosis pathway in Cd induced apoptosisin human promyelocytic leukemia HL-60 cells Howevercadmium adaptation may inhibit cell apoptosis allowingthereby the overproduction of critical mutations [122] Forthemanagement of the Cd2+ toxicity the natural antioxidantssuch as vitaminsC andE [123 124] aswell as other antioxidantmolecules like cysteine melatonin glutathione and ascor-bate under certain conditionsmay inducemoreDNAdamagein vitro [125]

7 Clinical and PathophysiologicalAspects of Cadmium Toxicity

71 Toxicity The EPA standard for maximum concentrationof Cd in drinking water is 5 ppb (120583gL) FDA has allowedCd in food coloring up to 15 ppb Due to its long half-life(10ndash30 years in humans) Cd after accumulation poses seriousthreat to human health Cd toxicity involves the organs suchas GI tract lungs kidney and bone as well as pulmonary andneurologic systems Cd causes neurotoxicity and alters brainmetabolism by alterations in the synthesis andormetabolismof biogenic amines and amino acid neurotransmitters inthe CNS These effects have been evidenced by differentexperimental protocols (in vivo and in vitro) in specificbrain regions Among the brain areas affected by cadmiumexposure hypothalamus is the most affected This region hasmultiple roles regulation of endocrine system and autonomicnervous system modulation of body temperature hunger-satiety emotional behavior and so forth

72 Clinical Symptoms People chronically exposed to cad-mium have headache sleep disorders and memory deficitsThese diseases are related to alterations in neurotransmitters(GABA serotonin) by altering GABAergic and serotoniner-gic systems Other symptoms include increased salivationchoking throat dryness cough chest pain restlessnessirritability nausea vomiting kidney dysfunction (glucosuriaproteinuria and aminoaciduria) itai-itai disease and renaland hepatic failures Pulmonary involvement includes pneu-monitis edema and bronchopneumonia Permanent lungdamage and cardiovascular collapse may occur Lung andprostate are the primary targets for the Cd induced cancer


73 Management Keeping the affected individuals awayfrom the source of Cd and chelation therapy through mela-tonin are the possible management practices suggested forcadmium toxicity Chelation therapy is however contraindi-cated because it exposes the kidney to large quantities ofnephrotoxic cadmium

8 Mercury

Mercury (Hg) occurs in nature in several physical andchemical forms all of which can produce toxic effects in highdoses It is a highly reactive and toxic transition elementIts zero oxidation state (Hg0) exists as vapor or as liquidmetal its cationic mercurous state Hg+ exists as inorganicsalts and its mercuric state Hg2+ may form either inorganicsalts or organomercury compoundsThese three groups varyin effects The different chemical forms of mercury includeelemental mercury vapor (Hg) inorganic mercurous (Hg II)mercuric (Hg III) and organic mercuric compounds [126]These forms have toxic effects in a number of organs suchas brain kidney and lungs [127] Mercury poisoning canresult in several diseases including acrodynia (pink disease)Hunter-Russell syndrome and Minamata disease Thoughthe specificmechanism of action of damage bymercury is notknown it has been shown that mercurous and mercuric ionsimpart their toxicological effects mainly through molecularinteractions by binding to the thiol groups present in differentmolecules such as GSH cysteine and metallothionene (MT)[128]

81 Elemental Mercury Quicksilver (liquid metallic mer-cury) is poorly absorbed by ingestion and skin contactIt is hazardous due to its potential to release mercuryvapour Animal data indicate that less than 001 of ingestedmercury is absorbed through the intact gastrointestinal tractthough it may not be true for individuals suffering fromileus (a disruption of the normal propulsive gastrointestinalmotor activity from nonmechanical mechanisms) Cases ofsystemic toxicity from accidental swallowing are rare andattempted suicide via intravenous injection does not appearto result in systemic toxicity Possibly the physical propertiesof liquid elemental mercury limit its absorption throughintact skin and in light of its very low absorption rate fromthe gastrointestinal tract skin absorption would not be high[129] In humans approximately 80 of inhaled mercuryvapor is absorbed via the respiratory tract where it enters thecirculatory system and is distributed throughout the bodyChronic exposure by inhalation even at low concentrationsin the range 07ndash42120583gm3 has been shown in case controlstudies to cause effects such as tremors impaired cognitiveskills and sleep disturbance in workers [130 131]

82 Inorganic Mercury Compounds Mercury in the inor-ganic form such as salts for example mercury (II) chlorideprimarily affects gastrointestinal tract and kidneys Sinceit cannot cross the BBB easily mercury salts inflict littleneurological damage without continuous or heavy exposureMercury (II) salts are usually more toxic than their mercury

(I) counterparts because of their greater solubility in waterand rapid absorption by the gastrointestinal tract [132]

83 Organic Mercury Compounds The organic compoundsofmercury tend to bemuchmore toxic than the element itselfand have been implicated in causing brain and liver damageThe most dangerous mercury compound dimethylmercuryis so toxic that even a small drop spilled on the skin or evena latex glove can cause death Methylmercury is the majorsource of organic mercury for all individuals [133] It entersthe food chain through bioaccumulation in the environmentreaching high concentrations among populations of somespecies Larger species of fish such as tuna or swordfishare usually of greater concern than smaller species Thiscompound in excess can cause coronary heart disease deathsand suboptimal neural development in children There is along latent period (up to 5 months) between exposure tomethylmercury and the appearance of symptoms in adultpoisoning cases No explanation for this long latent period isknown When the first symptom appears typically paresthe-sia (a tingling or numbness in the skin) it is followed rapidlyby more severe effects sometimes ending in coma and deathThe toxic damage appears to be determined by the peak valueof mercury not the length of the exposure It is cleared fromthe blood much more rapidly with a half-life of 7 to 10 daysand metabolized much more quickly than methylmercuryIt probably does not have methylmercuryrsquos ability to crossBBB via a transporter but instead relies on simple diffusion toenter the brain Other exposure sources of organic mercuryinclude phenylmercuric acetate and phenylmercuric nitrateThese were used in indoor latex paints for their antimildewproperties but were removed in 1990 because of cases oftoxicity [134]

84 Disposition and Toxicokinetics of Mercury The liquidmetallic mercury may be swallowed from a broken ther-mometer that is only slowly absorbed by the gastrointestinaltract (001) at a rate related to vaporization of the ele-mental mercury and is thought to be of no toxicologicalconsequence The vapor from metallic mercury is readilyabsorbed in the lungs Mercuryrsquos dissolved form is absorbedin the bloodstream and diffuses to all tissues of the bodyThe gastrointestinal absorption of compounds of mercuryfrom food is 15 as has been found in a study with humanvolunteers whereas absorption of methylmercury is of theorder of 90 to 95 The distribution of this heavy metalalso differs between red blood cells (RBCs) and plasma Forinorganic mercury the cell-to-plasma ratio ranges from lt1 to2 but for methylmercury it is about 10

Kidneys contain the greatest concentrations of mercuryfollowing exposure to inorganic salts ofmercury andmercuryvapor whereas organic mercury has a greater affinity for thebrain the posterior cortex in particular Mercury vapor alsohas greater predilection for the central nervous system thaninorganic mercury salts Excretion of mercury from the bodyis by way of urine and faeces which again differs for varyingforms of mercury dose and duration of exposure


85 Metabolic Transformation The elemental or metabolicmercury is oxidized to divalent mercury after absorptioninto the body tissues and is probably mediated by catalasesInhaled mercury vapor absorbed in the RBCs is transformedto divalent mercury but a portion is transported as metallicmercury to more distant tissues particularly the brain wherebiotransformation may occur

86 Therapy of Mercury Poisoning For acute inorganicmercury poisoning chelation therapy can be done withDMSA 23-dimercapto-1-propanesulfonic acid (DMPS) D-penicillamine (DPCN) or dimercaprol (BAL) [135] OnlyDMSA is FDA-approved for use in children for treatingmercury poisoning However several studies found no clearclinical benefit from DMSA treatment for poisoning due tomercury vapor No chelator for methylmercury or ethylmer-cury is approved by the FDA DMSA is the most frequentlyused chelator for severe methylmercury poisoning as it isgiven orally has fewer side effects and has been found tobe superior to BAL DPCN and DMPS Alpha-lipoic acid(ALA) has been shown to be protective against acutemercurypoisoning in severalmammalian specieswhen it is given soonafter exposure However the correct dosage is required asinappropriate dosages increase toxicity Although it has beenhypothesized that frequent low dosages of ALA may havepotential as a mercury chelator studies in rats have beencontradictory Glutathione and N-acetylcysteine (NAC) arerecommended by some physicians but have been shown toincreasemercury concentrations in the kidneys and the brainExperimental findings have demonstrated an interactionbetween selenium and methylmercury but epidemiologicalstudies have found little evidence that selenium helps protectagainst the adverse effects of methylmercury [136 137]Despite chelation therapy as advised in this case one of theimportant molecules that helps scavenging and reducing thetoxic effects of mercury is metallothionene which is a smalllow molecular weight protein and rich in sulfhydryl groups[126]

The clinical manifestations of neurotoxic effects are (1)paresthesia numbness and tightening sensation around themouth lips and extremities particularly the fingers and toes(2) ataxia a clumsy stumbling gait and difficulty in swal-lowing and articulating words (3) neurasthenia a generalizedsensation of weakness fatigue and inability to concentrate(4) vision and hearing loss (5) spasticity and tremor and (6)coma and death Neuropathologic observations have shownthat cortex of the cerebrum and cerebellum are selectivelyinvolved in focal necrosis of neurons lysis and phagocytosisand replacement by supporting glial cells These changesare more common to renal cell necrosis due to variouscauses Slight tubular cell injury manifested by enzymuriaand low molecular weight proteinuria may occur in workerswith low-level exposure to metallic mercury vapor [138]The toxicity of mercury in different organs of rat and themitochondria [139] has been reported

87 Mercury and Stress Proteins It is well established thatvarious stimuli including toxic chemicals enhance the syn-thesis of a class of proteins known as stress proteins [140]

This large superfamily of proteins collectively referred toas stress proteins include heat-shock proteins (hsps) andglucose-regulated proteins (grps) This particular stress-protein response has evolved as a cellular strategy to protectrepair and chaperone other essential cellular proteins Thedifferential expression of 4 HSPs has been observed in renalcortex and medulla of mercury treated rats [140]

88 Mercury and Cardiovascular Death Nearly ten yearsago based on clinical trials undertaken in Finland [141] itwas concluded that a high intake of mercury from nonfattyfreshwater fish and the consequent accumulation of mercuryin the body are associated with an excess risk of acutemyocardial infarction as well as death from coronary heartdisease cardiovascular disease The increased risk may bedue to the promotion of lipid peroxidation by mercury Inagreement with the conclusions of this trial were two recentepidemiological studies exploring possible participation ofmercury in myocardial infarction [142] This trial was relatedto the fish intake because fish is a major source of exposureto mercury It is assumed that the mercury content of fishmay counteract the beneficial effects of its 119899 minus 3 fatty acidsThe results led to the conclusion that the mercury levels weredirectly associated with the risk of myocardial infarctionand the adipose tissue DHA level was inversely associatedwith the risk Thus high mercury content may diminishthe cardioprotective effect of fish intake A similar trial wasconducted in order to investigate the association between theserum 119899 minus 3 end product fatty acids docosahexaenoic acid(DHA) docosapentaenoic acid (DPA) and eicosapentaenoicacid and the risk of acute coronary events in middle-agedmen (119899 = 1871) in Finland [143] The results displayed noassociation between the proportion of eicosapentaenoic acidand the risk of acute coronary events Both of the abovestudies concluded that fish oil derived fatty acids reduce therisk of acute coronary events However highmercury contentin fish could attenuate this protective effect

89 Mercury Induced Apoptosis It has been established thatapoptosis arises from the active initiation and propagationof a series of highly orchestrated specific biochemical eventsleading to the cell demise Being a normal physiological pro-cess it takes place in themaintenance of tissue homeostasis aswell as during embryonic development In apoptosis pathwayan array of diverse groups of molecules is involved Beinga network of complex cascade of reactions it functions toeliminate irreparably damaged cells or the unwanted cells It isimportant in this context that an inappropriate induction ofapoptosis by environmental agents may have broad rangingpathologic implications which could be associated withseveral diseases including cancer The toxicity of mercuryoccurs due to its high affinity to sulfhydryl groups of proteinsand enzymes and its ability to disrupt cell cycle progressionandor apoptosis in various tissues Recently a study toassess the potential of mercury to induce early and late-stage apoptosis in human liver carcinoma (HepG2) cells usingannexin-V and caspase 3 assays and flow cytometric analysisto determine the extent of phosphatidylserine externalization


and caspase 3 activation in HepG2 cells treated with subacutedoses of mercury (LD

5035 plusmn 06 120583gmL for mercury in

HepG2 cells) for 10 to 48 h established a dose responserelationship between mercury exposure and the degree ofearly and late-stage apoptosis in HepG2 cells The resultsindicated a gradual increase in apoptotic cells and caspasepositive cells with increasing doses of mercury [144]

9 Clinical and PathophysiologicalAspects of Mercury Toxicity

91 Toxicity There is rarely any toxicity of mercury due to itsexposure to elemental mercury The entry of mercury occursby way of inhalation of the vapor ingestion of the liquid orcutaneous exposure The metal is poorly absorbed in the gutand is eliminated in the feces Although in patients who havenormal GI mucosa toxicity rarely develops after ingestionpatients who have abnormal GI mucosa may absorb enoughmercury for toxicity to occur Occasionally mercury becomestrapped within the appendix but without signs of mercurytoxicity or appendicitis it can be safelymonitored and allowedto pass on its own If vomiting with subsequent aspiration ofelemental mercury occurs the risk for toxicity is increasedbecause mercury is well absorbed within the lungs Toxicityfrom elemental mercury occurs from inhalation of thevapor because mercury is well absorbed into the pulmonarycirculation allowing distribution to the brain kidneys gutand lungs Elemental mercury readily crosses BBB whereit concentrates in neuronal lysosomal dense bodies Themanifestations of elemental mercury toxicity have greatvariability depending on the chronicity of the exposureAcutetoxicity may manifest within hours of a large exposure withGI upset chills weakness cough and dyspnea with severecases developing adult respiratory distress syndrome andrenal failure

92 Clinical Symptoms Chronic mercury toxicity maydevelop over a period of weeks to months depending onthe level of exposure Initial symptoms commonly includeGI upset constipation abdominal pain and poor appetiteand may mimic a viral illness Other symptoms include drymouth headache andmuscle pains Chronic exposure resultsin two distinct clinical syndromes acrodynia and erethismKnown as pink disease Feer syndrome Feer-Swift diseaseerythroderma and raw-beef hands and feet acrodynia is acomplex of symptoms occurring in chronic toxicity fromelemental and inorganic mercury It occurs more commonlyin infants and children but it has been reported in adultsSymptoms include sweating hypertension tachycardia pru-ritus weakness poor muscle tone insomnia anorexia andan erythematous desquamating rash to the palms and solesOther symptoms in mouth include reddened swollen gumssubsequent mucosal ulcerations and possible tooth loss Byan unknown mechanism mercury may result in proximalweakness primarily involving the pelvic and pectoral girdlePatients who have mercury poisoning often develop char-acteristic personality changes collectively termed erethism

These patients may exhibit memory loss drowsiness with-drawal lethargy depression and irritability Another com-mon finding in mercury poisoning is incoordination and afine motor intention tremor primarily involving the handsMercury inhibits the enzyme catechol-o-methyltransferaseby inactivation of the coenzyme S-adenosyl methionineproducing elevated levels of catecholamines in the body Theincrease in catecholamines results in hypertension sweatingand tachycardia that may be clinically indistinguishablefrom pheochromocytoma A 24 h urine collection on thesepatients reveals elevated levels of urinary catecholaminesalthough typically to a lesser degree than that seen in trueneuroendocrine disease

93 Diagnosis The diagnosis of elemental mercury poison-ing involves incorporating clinical presentation (history andphysical findings) history of exposure and an elevated bodyburden ofmercury Bloodmercury levels have limited useful-ness because of mercuryrsquos short half-life in the blood Wholeblood mercury concentrations typically are lt10mgL Urinelevels are obtained more commonly in chronically exposedpatients with 24 h collections more reliable than spot urinelevels Normal levels typically arelt50mg ofmercury in a 24 hperiod Patients undergoing chelation therapy at the time ofcollection have elevated levels of mercury in a 24 h samplemaking interpretation difficult

94 Management Removal of the patient from the sourceof the toxic exposure is the most important interventionAs elemental mercury typically has minimal toxicity wheningested there is little role for GI decontamination Althoughchelation therapy is considered the mainstay of treatmentseveral controversies remain regarding its use Chelatorsare charged molecules capable of binding the metal ionforming a neutral complex excreted by the kidney Severalagents are available such as succimer dimercaprol and D-penicillamine Patients may require chelation for severalmonths depending on the total body burden of mercury Inpatients who have developed renal failure hemodialysis maybe requiredwith orwithout the inclusion of a chelation agent

10 Treatment for Heavy MetalsPoisoning by Chelation Therapy

Chelation therapy is the administration of chelating agents toremove heavy metals from the body Chelating agents wereintroduced into medicine as a result of the use of poisongas in World War I The term chelation comes from Greekword ldquochelaterdquo which means ldquoclawrdquo It must be emphasizedthat treatment is only a secondary alternative to reduction orprevention from exposure to toxic metals

Complexation is the formation of metal ion complexin which the metal ion is associated with a charged oruncharged electron donor referred to as a ligand The ligandmay be monodentate bidentate or multidentate that is itmay attach or coordinate using one two or more donoratoms Chelation occurs when bidentate ligands that includethe ligands forming ring structures bind to the metal ion


and the two-ligand atom attached to the metal Metal mayreact with Ominus Sminus and Nminus containing ligands present in theform of OH COOH SH NH

2 NH and N A resultant

metal complex is formed by coordinate bonds in whichboth electrons are contributed by the ligand [145] The firstexperimental use of a chelator against metal poisoning wasdone byKety and Letonoff [146]They attempted to use citrateas an antidote towards acute lead intoxication in 1941 Theconcept of chelation therapy relies on treating heavy metalintoxication bymobilization enabling it to pass through renalexcretion

Chelating agents vary in their specificity for toxic metalsIdeal chelating agents should be (1)water-soluble (2) resistantto biotransformation (3) able to reach sites of metal storagewithout causing any side effect and (4) capable of formingnontoxic complexes with toxic metals and of being excretedfrom the body and (5) they should also have a low affinityfor essential metals particularly calcium and zinc Severalchelating agents are available having different affinities fordifferent metals Common chelating agents include alpha-lipoic acid (ALA) aminophenoxyethane-tetraacetic acid(BAPTA) deferasirox deferiprone deferoxamine diethy-lene triamine pentaacetic acid (DTPA) dimercaprol (BAL)dimercaptopropane sulfonate (DMPS) dimercaptosuccinicacid (DMSA) ethylenediaminetetraacetic acid (calcium dis-odium versenate) (CaNa

2-EDTA) ethylene glycol tetraacetic

acid (EGTA) andD-penicillamine Some of the conventionalchelators their applications and side effects are describedhere A list of specific chelators used as drugs against toxicityinduced by corresponding heavy metals is presented inTable 3

11 BAL (British Anti-Lewisite)

BAL (23-dimercaptopropanol) as the first clinically usefulchelating agent was developed during World War II as aspecific antagonist to vesicant arsenical war gases based onthe observation that arsenic has an affinity for sulfhydryl-containing substances BAL a dithiol compound with twosulfur atoms on adjacent carbon atoms competes with thetoxic effects It was developed secretly as an antidote forLewisite the now-obsolete arsenic-based chemical warfareagent Today it is used medically in treatment of arsenicmercury lead and other toxicmetal poisoning In addition ithas in the past been used for the treatment ofWilsonrsquos diseasea genetic disorder in which the body tends to retain copper

In humans and experimental models BAL has beenshown to be the most effective antidote when administeredsoon after exposure Dimercaprol is itself toxic with anarrow therapeutic range and a tendency to concentratearsenic in some organs like brain [147] Other drawbacksinclude the need to administer it by painful intramuscularinjection because of its oily nature Serious side effects includenephrotoxicity and hypertension

BAL has been found to form stable chelates in vivo withmany toxic metals including inorganic mercury antimonybismuth cadmium chromium cobalt gold and nickelHowever it is not necessarily the treatment of choice for

toxicity to these metals BAL has been used as an adjunct inthe treatment of the acute encephalopathy of lead toxicity Itis a potentially toxic drug and its use may be accompaniedby multiple side effects Although treatment with BAL willincrease the excretion of cadmium there is a concomitantincrease in renal cadmium concentration so that its use incase of cadmium toxicity is to be avoided It does howeverremove inorganic mercury from the kidneys but it is notuseful in the treatment of alkyl mercury or phenyl mercurytoxicity BAL also enhances the toxicity of selenium andtellurium so it is not to be used to remove these metalsfrom the body Other side effects of BAL include vomitingheadache lachrymation rhinorrhea and salivation profusesweating intense pain in the chest and abdomen and anxiety[147 148]

12 DMPS

23-Dimercapto-1-propanesulfonic acid (abbreviated asDMPS) and its sodium salt (known as unithiol) are chelatingagents that form complexes with various heavy metals Theyare related to dimercaprol which is another chelating agentDMPS is a water-soluble derivative of BAL developed inresponse to BALrsquos toxicity and unpleasant side effects DPMShas been shown to reduce blood lead levels in children [149]It has an advantage over ethylenediaminetetraacetic acid(EDTA) which is that it is administered orally and doesnot appear to have toxic effects It has been widely usedin the former Soviet Union to treat many different metalintoxication cases DMPS has been used experimentallyto estimate the real burden of lead and inorganic mercury[150 151] Its effectiveness in mobilizing metals from thekidney may be because it is transported into kidney cells onthe organic anion transport system [150] It increases theurinary excretion of mercury in persons with an increasedbody burden from industrial exposure dentists and dentaltechnicians persons with dental amalgams and thoseexposed to mercurous chloride in skin creams [151 152]

13 meso-23-Dimercaptosuccinic Acid (DMSA)

DMSA is a chemical analog of BAL More than 90 percent ofDMSA is in the form of amixed disulfide in which each of thesulfur atoms is in disulfide linkage with a cysteine moleculeThe drug is of current interest clinically because of its abilityto lower blood and lead levels It has advantages over EDTAbecause it is given orally and has greater specificity for lead Itmay be safer than EDTA in that it does not enhance excretionof calcium and zinc to the same degree Studies in rodentsshowed that a single dose of DMSA primarily removes leadfrom soft tissues [153] DMSA possesses low toxicity uponoral administration and no redistribution of metal from oneorgan to another [154 155] Animal studies suggested thatDMSA is an effective chelator of soft tissues but it is unableto chelate lead from bones [154] DMSA is not known tocause elevations in the excretion of calcium zinc or ironalthough zinc excretion increases to 18 times baseline duringtreatment


Table 3 Protein thiol-disulfide oxidoreductases with their substrates and functions

Enzyme Substrates FunctionGlutaredoxin (Grx) PSSG AntioxidantSulfiredoxin (Srx) PSSG ReductantGSSG reductase (GR) GSSG Antioxidant maintains GSHThioredoxin (Trx) PSSP Reductasea antioxidantTrx reductase (TR) Trx-S2 Reduces TrxProtein disulfide isomerase (PDI) PSHb Protein foldingProtein thiol-disulfide oxidoreductasesaCofactor for ribonucleotide reductasebOxidizing

14 Calcium Disodium Ethylenediaminete-traacetic Acid (CaNa

2EDTA)

This is a colourless water-soluble solid which is producedon a large scale for many applications Its prominence as achelating agent arises from its ability to ldquosequesterrdquo di- andtricationic metal ions such as Ca2+ and Fe3+ After beingbound by EDTA metal ions remain in solution but exhibitdiminished reactivity Calcium salt of ethylenediaminete-traacetic acid (EDTA) must be used for clinical purposesbecause the sodium salt has greater affinity for calcium andwill produce hypocalcemic tetany CaNa

2EDTA is a deriva-

tive of ethylenediaminetetraacetic acid (EDTA) syntheticpolyaminocarboxylic acid [156] EDTA exhibits low toxicitywith LD

50(rat) of 20ndash22 g kgminus1 It has been found to be

both cytotoxic and weakly genotoxic in laboratory animalsOral exposures have been noted to cause reproductive anddevelopmental effects CaNa

2EDTA cannot pass through

cellular membrane so its application can help remove themetal ions present in extracellular fluid Further EDTAtreatment can result in mobilization of lead from hard tissuedeposit to soft organs [157 158] The calcium salt of EDTAhas been shown to cause necrosis of renal tubular cellsThesedrawbacks preclude application of CaNa

2EDTA as a suitable

drug to treat lead poisoning

15 Vitamins C and E

Vitamin C or L-ascorbic acid is an essential nutrient and apotential antioxidant for humans It is made internally byalmost all organisms with humans being a notable exceptionThe pharmacophore of this vitamin is an ascorbic anionIn humans vitamin C is essential to a healthy diet as wellas being a highly effective antioxidant acting to lessenoxidative stress and a substrate for ascorbate peroxidase andan enzyme cofactor for the biosynthesis of many importantbiochemicals Vitamin C acts as an electron donor for eightdifferent enzymes It also acts as a scavenger of free radicaland plays an important role in regeneration of 120572-tocopherol[159] The plasma ascorbate concentration in oxidative stresspatient (less than 45120583mol Lminus1) measured is lower thanhealthy individual (614ndash80 120583mol Lminus1)The increasing plasmaascorbate level may have therapeutic effects in oxidativestress individual Individual with oxidative stress and healthyindividual have different pharmacokinetics of ascorbate

Ascorbic acid behaves not only as antioxidant but also asa prooxidant Ascorbic acid reduced transition metals suchas cupric ions (Cu2+) to cuprous (Cu1+) and ferric ions(Fe3+) to ferrous (Fe2+) during conversion from ascorbateto dehydroxyascorbate This reaction in vitro can generatesuperoxide and other ROS However in the body freetransition elements are unlikely to be present while iron andcopper are bound to diverse proteins Recent studies showthat intravenous injection of 75 g of ascorbate daily for 6 daysdid not increase prooxidant markers Thus ascorbate as aprooxidant is unlikely to convertmetals to create ROS in vivoThere are few side effects of vitamin C when taken in excesssuch as diarrhea iron poisoning hemolytic anemia kidneystone formation and suppression of progesterone in pregnantladies

Vitamin E (120572-tocopherol) is the collective name fora set of 8 related 120572- 120573- 120574- and 120575-tocopherols and thecorresponding four tocotrienols which are fat-soluble vita-mins with antioxidant properties Vitamin E also providesprotection against silver induced lesions When Cd wascoadministered with vitamin E the results showed reducedaccumulation of cadmium in the kidney liver and bloodTheantioxidants levels enhanced by Cd induction came down tonear normal levels which indicate that antioxidant propertiesof vitamin E may be responsible for providing protectionfrom cadmium toxicity [160] Vitamin E has been shown toreduce lipid peroxidation and to increase the cell viabilityThe supplementation of vitamin E to Pb-treated erythrocyteshas been shown to prevent the inhibition of 120575-aminolevulinicdehydratase activity and lipid oxidation [161] in vivo and invitro Vitamin E could also be useful to protect membrane-lipids and proteins from oxidation due to lead intoxication

16 120573-Carotene

120573-Carotene is fat-soluble organic compound a terpenoida red-orange pigment abundant in plants and fruits As acarotene with 120573-rings at both ends it is the most commonform of carotene It is a precursor (inactive form) of vitaminA (retinol) The most common side effect of high dosesof 120573-carotene consumption is carotenodermia a harmlesscondition that presents as a conspicuous orange skin tintarising from deposition of the carotenoid in the outermostlayer of the epidermis It has also been associated withincreased rate of lung cancer among those who smoke [162]


17 N-Acetylcysteine (NAC)

N-acetylcysteine or N-acetyl-L-cysteine (NAC) a pharma-ceutical drug marketed with various trade names is usedmainly as a mucolytic agent and in the management ofparacetamol (acetaminophen) overdose Out of the threesulfur-containing amino acids L-cysteine is an essential oneas the other two may be synthesized by using it L-cysteinehas been shown to act as an antioxidant and has a pivotalrole in endogenous free radicals induced intoxication inthe body The exposure to heavy metals has been found toreduce level of cysteine [163] Recently it has been reportedthat a high oral dose of NAC modulates inflammation incystic fibrosis (CF) and has the potential to counter theintertwined redox and inflammatory imbalances in CF [164]The supplementation of NAC may attenuate Cd inducednephrotoxicity via chelation [165] The coadministration ofNAC and DMSO after arsenic exposure leads to removal ofarsenic from soft organs [45] NAC was metabolized to S-nitroso-N-acetylcysteine (SNOAC) which increased bloodpressure inmice treated with acetylcysteine So its large dosescan damage the heart and lungs

18 120572-Lipoic Acid

Lipoic acid is an organosulfur compound (yellow solid) ItsR-enantiomer is an essential cofactor for many enzyme com-plexes This is a carboxylic acid and features a cyclic disulfideor ditholane ring functional group It exists as dihydrolipoicacid the reduced form of lipoic acid intracellularly Lipoicacid was first postulated to be an effective endogenous thiolantioxidant when it was found to prevent the symptoms ofvitamin C and vitamin E deficiency Dihydrolipoic acid isable to regenerate (reduce) antioxidants such as glutathionevitamin C and vitamin E It is equipped with properties toquench ROS in vitro The relatively good scavenging activityof lipoic acid is due to the strained conformation of the5-membered ring in the intramolecular disulfide Owingto the presence of two thiol groups it can chelate metalssuch as iron copper mercury and cadmium and remediatefree radical damage in biological system [166] It is readilyavailable from the diet and absorbed through the gut andcan easily enter BBB in humans unlike DMSA and DMPSHowever its effectiveness is heavily dependent on the dosageand frequency of application The exogenous supplementa-tion of LA has been reported to act as an efficient antioxidantthereby reducing oxidative stress both in vitro and in vivo[167] Its intake can change the redox level of tissues directlyby quenching the free radicals and indirectly by enhancingthe levels of other antioxidantsantioxidant enzymes Amongthe mono- and dithiols (glutathione cysteine dithiothreitoland lipoic acid) LA has been reported in vitro to be the mostpotent scavenger of free radicals generated during cadmiumhepatotoxicity [168]

19 Melatonin

Melatonin chemically known as N-acetyl-5-methoxytryptamine is a naturally occurring hormone found in most

animals including humans and some other living organismsincluding algae It is produced by the pineal gland (outsideBBB) under the influence of the suprachiasmatic nuclei(SCN) of the hypothalamus which receives informationfrom the retina about the daily pattern of light and darknessIts circulating levels vary in a daily cycle Despite itsrole in regulating circadian rhythm (synchronization ofthe biological clock) in humans it also acts as powerfulendogenous scavenger of ROS and RNS such as OH O

2

minusand NO radicals Melatonin is an antioxidant that caneasily cross cell membranes and BBB Melatonin is a directscavenger of ROS Unlike other antioxidants melatonin doesnot undergo redox cycling Redox cycling may allow otherantioxidants (such as vitamin C) to regain their antioxidantproperties Melatonin on the other hand once oxidizedcannot be reduced to its former state because it formsseveral stable end-products upon reacting with free radicalsTherefore it has been referred to as a terminal (or suicidal)antioxidant

Melatonin helps maintain membrane fluidity by prevent-ing LPO and scavenging ROS and RNS [169] Its capacity toabsorb free radicals extends at least to the quaternarymetabo-lites of melatonin a process referred to as ldquothe free radicalscavenging cascaderdquo Due to antioxidant potential attachedto melatonin it has been found to protect haematopoieticcells from the lead-induced damage [170] The indole grouppresent in the melatonin has been implicated in protectionof thiol groups of membrane proteins from lead toxicity[156 171 172]

As reported melatonin stimulates antioxidative enzymessuch as GPx and SOD and quickly eliminates H

2O2from rat

brain cortical cells [173 174] It also enhances the productionof the enzymes involved in glutathione synthesis [175] Thecirculating melatonin decreases with age and in recent yearsmuch interest has been focused on its immunomodulatoryeffectMelatonin stimulates the production of progenitor cellsfor granulocytes macrophages It also stimulates the produc-tion of NK cells and CD4+ cells and inhibits CD8+ cells Theproduction and release of various cytokines from NK cellsand T-helper lymphocytes also are enhanced by melatoninMelatonin presumably regulates immune function by actingon the immune-opioid network by affecting G protein-cAMPsignal pathway and by regulating intracellular glutathionelevels [176] Melatoninrsquos antioxidative property may offerprotection against carcinogenesis neurodegeneration andaging [177 178]

Possibly there are three different mechanisms of actionsof melatonin (1) melatonin could trigger antioxidant cellularmechanisms (2) melatonin could form a complex joiningthe cadmium and thus avoid the uptake of the metal and itsharmful effects a fact shown at the brain and pituitary leveland (3) melatonin is very liposoluble so it can diffuse freelyand cross all cellular barriers facilitating the elimination ofcadmium from tissues In conclusion melatonin is a naturalantioxidant with high power of scavenger of free radicals soit can play an important role in protecting cells against theoxidative damage induced by cadmiumThusmelatoninmaybe a good tool to palliate at least in part the toxicity of thismetal [179]


The physical chemical clinical and treatment aspects ofarsenic lead cadmium and mercury have been summarisedin Table 2

20 Combination Therapy

Combination therapy most often not only is used to referto the simultaneous administration of two or more med-ications to treat a single disease but also is used whenother types of therapy are employed at the same timeHere in chelation therapy it refers to the administration oftwo chelators differently administered with the notion thatvarious chelating agents may immobilize (trap) the toxicmetals from different tissues to render better protection fromtheir toxicity [180ndash184] In combination chelation therapyalso the coadministration of dietary nutrients like vitaminsfor example thiamine [183] an essential metal such as zinc[180 185] or an amino acid like methionine with a chelatingagent has been found to render better clinical recoveries aswell as mobilization of lead from the tissues [186 187]

21 Conclusion

The heavy metals thus exhibit the ability to induce oxidativestress by generating ROS Oxidative stress due to heavymetals is the outcome of a negative shift of the balancebetween the production of ROS and the ability of thebiological systems to readily counteract the ROS mediateddamage or repair of it rapidly The heavy metals toxicityis caused either by their direct binding with thiol groupsof the proteinsenzymes thereby causing perturbations intheir three-dimensional conformations or by replacing thedivalent metal ions from their catalytic pocket which areessentially required by concerned proteinsenzymes as cofac-tors for their optimal activity In either of these situationsthese biomolecules tend to lose their native characteristicsdue to unfolding or denaturation and then their functionsare greatly compromised which lead to serious bearings ontotheir biological activity and finally the cellular health Allforms of life maintain a reducing environment within theircells This reducing environment is preserved by enzymesthat maintain the reduced state through a constant input ofmetabolic energy Disturbances in this normal redox stateby heavy metals can cause toxic effects indirectly throughthe production of peroxides and free radicals that induceoxidative stress which is responsible for the damage of severalkey components of the cells including proteins lipid andDNA This phenomenon culminates into onset of severalknownunknown diseases in humans The application ofnumber of chelating organic molecules is being tried withthe expectation that they would make coordinate complexeswith these heavy metals and help remove them from theirharbour making the organ or tissue free from metalrsquos burdenand toxicity This attempt however gets compromised withserious side effects of such chelating drugs Although coad-ministration of antioxidants (natural herbal or synthetic) orwith another chelating agents has shown to improve removalof toxic metals from the system as well as clinical recoveries

in animal models still the in-depth clinical studies with pre-existing or newer chelating agents are required to be done toreap real benefitwith the least side effects during combinationtherapy in association with those of antioxidants In case ofhumans it is also important to find out the suitable doseand duration of treatment to decide the optimal therapeuticindex for any of the drugs to be given in isolation or indifferent combinations as explained above In conclusion thepresent stage of knowledge about the impact of heavy metalsin biological systems indicates that enhanced formation offree radicals and ROS or RNS or their intermediates can beregarded as a common factor in determining heavy metal-induced toxicity and carcinogenicity

Conflict of Interests

The authors declare that they do not have any conflict ofinterests

References

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[2] S S Leonard G K Harris and X Shi ldquoMetal-induced oxida-tive stress and signal transductionrdquo Free Radical Biology andMedicine vol 37 no 12 pp 1921ndash1942 2004

[3] M Valko H Morris andM T D Cronin ldquoMetals toxicity andoxidative stressrdquoCurrentMedicinal Chemistry vol 12 no 10 pp1161ndash1208 2005

[4] F ChenMDingVCastranova andX Shi ldquoCarcinogenicmet-als and NF-120581B activationrdquoMolecular and Cellular Biochemistryvol 222 no 1-2 pp 159ndash171 2001

[5] S J S Flora M Mittal and A Mehta ldquoHeavy metal inducedoxidative stress amp its possible reversal by chelation therapyrdquoIndian Journal of Medical Research vol 128 no 4 pp 501ndash5232008

[6] A C Porter G R Fanger and R R Vaillancourt ldquoSignaltransduction pathways regulated by arsenate and arseniterdquoOncogene vol 18 no 54 pp 7794ndash7802 1999

[7] NCR Arsenic in Drinking Water National academy PressWashington DC USA 1999

[8] A H Smith C Hopenhayn-Rich M N Bates et al ldquoCancerrisks from arsenic in drinking waterrdquo Environmental HealthPerspectives vol 97 pp 259ndash267 1992

[9] J J Hostynek R S Hinz C R LorenceM Price and RHGuyldquoMetals and the skinrdquo Critical Reviews in Toxicology vol 23 no2 pp 171ndash235 1993

[10] P E Morrow H Beiter F Amato and F R Gibb ldquoPulmonaryretention of lead an experimental study inmanrdquoEnvironmentalResearch vol 21 no 2 pp 373ndash384 1980

[11] M PWaalkes J Liu JMWard and B A Diwan ldquoMechanismsunderlying arsenic carcinogenesis hypersensitivity of miceexposed to inorganic arsenic during gestationrdquo Toxicology vol198 no 1ndash3 pp 31ndash38 2004

[12] T C Lee N Tanaka PW Lamb T M Gilmer and J C BarrettldquoInduction of gene amplification by arsenicrdquo Science vol 241no 4861 pp 79ndash81 1988

[13] J Pi S Horiguchi Y Sun et al ldquoA potential mechanism forthe impairment of nitric oxide formation caused by prolonged


oral exposure to arsenate in rabbitsrdquo Free Radical Biology andMedicine vol 35 no 1 pp 102ndash113 2003

[14] E Puccetti and M Ruthardt ldquoAcute promylocytic leukemiaPMLRAR

120572and the lukemic stem cellrdquo Lukemia vol 18 no 7

pp 1169ndash1175 2004[15] E Guillamet A Creus J Ponti E Sabbioni S Fortaner and

R Marcos ldquoIn vitro DNA damage by arsenic compounds in ahuman lymphoblastoid cell line (TK6) assessed by the alkalinecomet assayrdquoMutagenesis vol 19 no 2 pp 129ndash135 2004

[16] C Huang J Li M Ding et al ldquoArsenic-induced NF120581B transac-tivation through Erks- and JNKs-dependent pathways inmouseepidermal JB6 cellsrdquo Molecular and Cellular Biochemistry vol222 no 1-2 pp 29ndash34 2001

[17] A M Bode and Z Dong ldquoThe paradox of arsenic molecu-lar mechanisms of cell transformation and chemotherapeuticeffectsrdquo Critical Reviews in OncologyHematology vol 42 no1 pp 5ndash24 2002

[18] C S Huang A M Bode N Y Chen et al ldquoTransactivation ofAP-1 in AP-1-luciferase reporter transgenicmice by arsenite andarsenaterdquo Anticancer Research vol 21 no 1 pp 261ndash267 2001

[19] M Cavigelli W W Li A Lin B Su K Yoshioka and MKarin ldquoThe tumor promoter arsenite stimulates AP-1 activityby inhibiting a JNK phosphataserdquo The EMBO Journal vol 15no 22 pp 6269ndash6279 1996

[20] A C Newton ldquoProtein kinase C seeing two domainsrdquo CurrentBiology vol 5 no 9 pp 973ndash976 1995

[21] P Kapahi T Takahashi G Natoli et al ldquoInhibition of NF-120581Bactivation by arsenite through reaction with a critical cysteinein the activation loop of I120581B kinaserdquo Journal of BiologicalChemistry vol 275 no 46 pp 36062ndash36066 2000

[22] H K Koul M Pal and S Koul ldquoRole of p38MAP kinase signaltransduction in solid tumorsrdquo Genes amp Cancer vol 4 no 9-10pp 342ndash359 2013

[23] J Sun M Yu Y Lu et al ldquoCarcinogenic metalloid arsenicinduces expression of mdig oncogene through JNK and STAT3activationrdquo Cancer Letters vol 346 pp 257ndash263 2014

[24] H Shi X Shi and K J Liu ldquoOxidative mechanism of arsenictoxicity and carcinogenesisrdquo Molecular and Cellular Biochem-istry vol 255 no 1-2 pp 67ndash78 2004

[25] K Rin K Kawaguchi K Yamanaka M Tezuka N Oku andS Okada ldquoDNA-Strand breaks induced by dimethylarsinicacid a metabolite of inorganic arsenics are strongly enhancedby superoxide anion radicalsrdquo Biological and PharmaceuticalBulletin vol 18 no 1 pp 45ndash48 1995

[26] K Yamanaka F Takabayashi M Mizoi Y An A Hasegawaand S Okada ldquoOral exposure of dimethylarsinic acid a mainmetabolite of inorganic arsenics in mice leads to an increasein 8-oxo-21015840-deoxyguanosine level specifically in the targetorgans for arsenic carcinogenesisrdquo Biochemical and BiophysicalResearch Communications vol 287 no 1 pp 66ndash70 2001

[27] H Kolb and V Kolb-Bachofen ldquoType I insulin dependentdiabetes mellitus and nitric oxiderdquo Diabetologia vol 35 no 8pp 796ndash797 1992

[28] J W Baynes ldquoRole of oxidative stress in development ofcomplications in diabetesrdquoDiabetes vol 40 no 4 pp 405ndash4121991

[29] D Giugliano A Ceriello and G Paolisso ldquoOxidative stress anddiabetic vascular complicationsrdquo Diabetes Care vol 19 no 3pp 257ndash267 1996

[30] P S vanDam B S van Asbeck DW Erkelens J J MMarxWGispen and B Bravenboer ldquoThe role of oxidative stress in neu-ropathy and other diabetic complicationsrdquoDiabetesMetabolismReviews vol 11 no 3 pp 181ndash192 1995

[31] A Parthiban S Vijayalingam K R Shanmugasundaram andR Mohan ldquoOxidative stress and the development of diabeticcomplicationsmdashantioxidants and lipid peroxidation in erythro-cytes and cell membranerdquo Cell Biology International vol 19 no12 pp 987ndash993 1995

[32] J R Williamson K Chang M Frangos et al ldquoHyperglycemicpseudohypoxia and diabetic complicationsrdquo Diabetes vol 42no 6 pp 801ndash813 1993

[33] J Nourooz-Zadeh A Rahimi J Tajaddini-Sarmadi et alldquoRelationships between plasmameasures of oxidative stress andmetabolic control in NIDDMrdquo Diabetologia vol 40 no 6 pp647ndash653 1997

[34] M S Brenda L G Peter and J Kenneth ldquoThe role of generalmetal specific cellular responses in protection and repair ofmetal induced damage stress proteins andmetallothioneinsrdquo inToxicology of Metals L W Chang Ed chapter10 p 167 Lewis1996

[35] C Inada K Yamada N Takane and K Nonaka ldquoPoly(ADP-ribose) synthesis induced by nitric oxide in amouse 120573-cell linerdquoLife Sciences vol 56 no 18 pp 1467ndash1474 1995

[36] V Borcea J Nourooz-Zadeh S P Wolff et al ldquo120572-Lipoic aciddecreases oxidative stress even in diabetic patients with poorglycemic control and albuminuriardquo Free Radical Biology andMedicine vol 26 no 11-12 pp 1495ndash1500 1999

[37] T J Lyons ldquoOxidized low density lipoproteins a role in thepathogenesis of atherosclerosis in diabetesrdquoDiabetic Medicinevol 8 no 5 pp 411ndash419 1991

[38] J A Sinclair ldquoFree radical mechanisms and vascular compli-cation of diabetes mellitusrdquo Diabetes Reviews vol 2 pp 7ndash101993

[39] T J Lyons ldquoLipoprotein glycation and its metabolic conse-quencesrdquo Diabetes vol 41 no 2 pp 67ndash73 1992

[40] J Tibbetts How Arsenic Acts Evidence of Oxidative StressScience Selections 2002

[41] K Iwama S Nakajo T Aiuchi and K Nakaya ldquoApoptosisinduced by arsenic trioxide in leukemia U937 cells is dependenton activation of p38 inactivation of ERK and the Ca2+-dependent production of superoxiderdquo International Journal ofCancer vol 92 no 4 pp 518ndash526 2001

[42] S Lynn J R Gurr H T Lai and K Y Jan ldquoNADHoxidase acti-vation is involved in arsenite-induced oxidativeDNAdamage inhuman vascular smoothmuscle cellsrdquoCirculation Research vol86 no 5 pp 514ndash519 2000

[43] G A Bongiovanni E A Soria and A R Eynard ldquoEffectsof the plant flavonoids silymarin and quercetin on arsenite-induced oxidative stress in CHO-K1 cellsrdquo Food and ChemicalToxicology vol 45 no 6 pp 971ndash976 2007

[44] EMKenyon andM FHughes ldquoA concise reviewof the toxicityand carcinogenicity of dimethylarsinic acidrdquo Toxicology vol160 no 1ndash3 pp 227ndash236 2001

[45] A Santra A Chowdhury S Ghatak A Biswas andG K DhalildquoArsenic induces apoptosis in mouse liver is mitochondriadependent and is abrogated by N-acetylcysteinerdquo Toxicologyand Applied Pharmacology vol 220 no 2 pp 146ndash155 2007

[46] H V Aposhian and M M Aposhian ldquoArsenic toxicology fivequestionsrdquo Chemical Research in Toxicology vol 19 no 1 pp1ndash15 2006


[47] S A Stice Speciation Metabolism toxicity and protein-bindingof different arsenic species in human cells [Electronic The-ses and Dissertations] FIU 2014 httpdigitalcommonsfiueduetd1203

[48] B Das S Mandal and K Chaudhuri ldquoRole of arginine acomponent of aqueous garlic extract in remediation of sodiumarsenite induced toxicity in A375 cellsrdquo Toxicology Research no3 pp 191ndash196 2014

[49] S Bhattacharjee C Sarkar and S Pal ldquoAdditive beneficial effectof folic acid and vitamin B12 co-administration on arsenic-induced oxidative damage in cardiac tissue in vivordquo AsianJournal of Pharmaceutical and Clinical Research vol 6 no 1 pp64ndash69 2013

[50] H Ghasemi F Rostampour and A Ranjbar ldquoThe role ofoxidative stress inmetals toxicitymitochondrial dysfunction asa key playerrdquo Galen Medical Journal vol 3 pp 2ndash13 2013

[51] C Nava-Ruız and M Mendez-Armenta ldquoCadmium lead thal-lium occurrence neurotoxicity and histopathological changesof the nervous systemrdquo in Pollutant Diseases Remediation andRecycling vol 4 of Environmental Chemistry for a SustainableWorld pp 321ndash349 Springer 2013

[52] N Qureshi and R Sharma ldquoLead toxicity and infertility infemale Swiss mice a reviewrdquo Journal of Chemical Biological andPhysical Sciences vol 2 pp 1849ndash1861 2012

[53] O Boucher M J Burden G Muckle et al ldquoResponse inhibi-tion and error monitoring during a visual GoNo-Go task inInuit children exposed to lead polychlorinated biphenyls andmethylmercuryrdquo Environmental Health Perspectives vol 120no 4 pp 608ndash615 2012

[54] E Vallascas A de Micco F Deiana S Banni and E SannaldquoAdipose tissue another target organ for lead accumulation Astudy on sardinian children (Italy)rdquoAmerican Journal ofHumanBiology vol 25 no 6 pp 789ndash794 2013

[55] Y Li S Wu Y Xiang and X Liang ldquoAn investigation ofoutpatient childrenrsquos blood lead level in Wuhan Chinardquo PLoSONE vol 9 no 4 Article ID e95284 2014

[56] M D Pulido and A R Parrish ldquoMetal-induced apoptosismechanismsrdquo Mutation Research vol 533 no 1-2 pp 227ndash2412003

[57] L H Mason ldquoPb neurotoxicity neuropsychological effects oflead toxicityrdquo BioMed Research International vol 2014 ArticleID 840547 8 pages 2014

[58] P Grandjean ldquoNeurobehavioural effects of developmental tox-icityrdquoThe Lancet Neurology vol 13 pp 330ndash338 2014

[59] R A Goyer and B C Rhyne ldquoPathological effects of leadrdquoInternational Review of Experimental Pathology vol 12 pp 1ndash77 1973

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[61] R A Goyer ldquoLead toxicity current concernsrdquo EnvironmentalHealth Perspectives vol 100 pp 177ndash187 1993

[62] B J Heard ldquoNon-toxic and frangible bulletsrdquo in ForensicBallistics in Court Interpretaion and Presentation of Fire ArmsB J Heard Ed Wiley Publishing Science New York NY USA2014

[63] CDC ldquoCDC response to advisory committee on childhoodlead poisoning prevention recommendationsrdquo in Low LevelLead Exposure Harms Children A Renewed Call of PrimaryPrevention US Department of Health and Human ServicesCDC Atlanta Ga USA 2012

[64] R L Jones D M Homa P A Meyer et al ldquoTrends in bloodlead levels and blood lead testing among US children aged 1 to5 years 1988ndash2004rdquo Pediatrics vol 123 no 3 pp e376ndashe3852009

[65] A Florea and D Busselberg ldquoOccurrence use and potentialtoxic effects of metals and metal compoundsrdquo BioMetals vol19 no 4 pp 419ndash427 2006

[66] B P Lanphear K Dietrich P Auinger and C Cox ldquoCognitivedeficits associated with blood lead concentrations iexcl10120583gdL inUS children and adolescentsrdquo Public Health Reports vol 115 no6 pp 521ndash529 2000

[67] ATSDRToxicological Profile of Lead US Department of Healthand Human Services Agency for Toxic Substances and DiseaseRegistry Washington DC USA 1999

[68] R S Hellberg C A M Dewitt and M T Morrissey ldquoRisk-benefitAnalysis of seafood consumption a reviewrdquoComprehen-sive Reviews in Food Science and Food Safety vol 11 no 5 pp490ndash517 2012

[69] I Lancranjan H I Popescu O Gavanescu I Klepsch and MSerbanescu ldquoReproductive ability of workmen occupationallyexposed to leadrdquo Archives of Environmental Health vol 30 no8 pp 396ndash401 1975

[70] H A Ruff M E Markowitz P E Bijur and J F RosenldquoRelationships among blood lead levels iron deficiency andcognitive development in two-year-old childrenrdquo Environmen-tal Health Perspectives vol 104 no 2 pp 180ndash185 1996

[71] G Lockith ldquoBlood lead levels in childrenrdquo Canadian MedicalAssociation Journal vol 149 pp 139ndash142 1993

[72] S J Yiin andTH Lin ldquoLead-catalyzed peroxidation of essentialunsaturated fatty acidrdquo Biological Trace Element Research vol50 no 2 pp 167ndash172 1995

[73] K K Bokara E Brown R McCormick P R Yallapragada SRajanna andR Bettaiya ldquoLead-induced increase in antioxidantenzymes and lipid peroxidation products in developing ratbrainrdquo BioMetals vol 21 no 1 pp 9ndash16 2008

[74] B O Adegbesan and G A Adenuga ldquoEffect of lead expo-sure on liver lipid peroxidative and antioxidant defense sys-tems of protein-undernourished ratsrdquo Biological Trace ElementResearch vol 116 no 2 pp 219ndash225 2007

[75] R E Ummus J Onuki D Dornemann H G Marisa and DMMedeiros Paolo ldquoA free radical hypothesis of lead poisoningand inborn porphyries Associated with 5-aminolevulinic acidoverloadrdquo Quımica Nova vol 16 pp 385ndash392 1996

[76] I Baranowska-Bosiacka V Dziedziejko K Safranow et alldquoInhibition of erythrocyte phosphoribosyltransferases (APRTand HPRT) by Pb2+ a potential mechanism of lead toxicityrdquoToxicology vol 259 no 1-2 pp 77ndash83 2009

[77] G Rausa ldquoBehavior of erythrocytes glucose 6- phosphatedehydrogenase in rats treated subcutaneously with lead acetaterdquoChemical Abstracts vol 71 p 125 1969

[78] V Calderon Salinas C Hernandez-Luna M Maldonado andD Saenz ldquoMechanisms of the toxic effect of lead I Free leadin erythrocyterdquo Journal of Exposure Analysis and EnvironmentalEpidemiology vol 3 pp 153ndash164 1993

[79] L E Rogers N D Battles E W Reimold and P SartainldquoErythrocyte enzymes in experimental lead poisoningrdquo Archivfur Toxikologie vol 28 no 3 pp 202ndash207 1971

[80] B S Glenn W F Stewart B S Schwartz and J BresslerldquoRelation of alleles of the sodium-potassium adenosine triphos-phatase 1205722 gene with blood pressure and lead exposurerdquo TheAmerican Journal of Epidemiology vol 153 no 6 pp 537ndash5452001


[81] S J S Flora G Flora and G Saxena ldquoEnvironmental occur-rence health effects and management of lead poisoningrdquo inLead Chemistry Analytical Aspects Environmental Impacts andHealth Effects S B Cascas and J Sordo Eds pp 158ndash228Elsevier Publication Amsterdam The Netherlands 2006

[82] S E Chia E Yap and K S Chia ldquo120575-amino leviulinic aciddehydrate (ALAD) polymorphism and susceptibility of workersexposed to inorganic lead and its effect on neurobehavioralfunctionsrdquo NeuroToxicology vol 25 no 6 pp 1041ndash1047 2004

[83] G O NoriegaM L Tomaro and AM C Del Batlle ldquoBilirubinis highly effective in preventing in vivo 120575-aminolevulinic acid-induced oxidative cell damagerdquo Biochimica et Biophysica Acta -Molecular Basis of Disease vol 1638 no 2 pp 173ndash178 2003

[84] Y Zhao L Wang H B Shen Z X Wang Q Y Wei andF Chen ldquoAssociation between 120575-aminolevulinic acid dehy-dratase (ALAD) polymorphism and blood lead levels a meta-regression analysisrdquo Journal of Toxicology and EnvironmentalHealth A vol 70 no 23 pp 1986ndash1994 2007

[85] S E Chia E Yap and K S Chia ldquo120575-aminolevulinic acid dehy-dratase (ALAD) polymorphism and susceptibility of workersexposed to inorganic lead and its effects on neurobehavioralfunctionsrdquo NeuroToxicology vol 25 no 6 pp 1041ndash1047 2004

[86] J Bressler KKimTChakraborti andGGoldstein ldquoMolecularmechanisms of leadneurotoxicityrdquoNeurochemical Research vol24 no 4 pp 595ndash600 1999

[87] M Damek-Poprawa and K Sawicka-Kapusta ldquoHistopatholog-ical changes in the liver kidneys and testes of bank volesenvironmentally exposed to heavy metal emissions from thesteelworks and zinc smelter in Polandrdquo Environmental Researchvol 96 no 1 pp 72ndash78 2004

[88] F Khalil-Manesh H C Gonick E W J Weiler B Prins M AWeber and R E Purdy ldquoLead-induced hypertension possiblerole of endothelial factorsrdquo American Journal of Hypertensionvol 6 no 9 pp 723ndash729 1993

[89] T Sanders Y Liu V Buchner and P B Tchounwou ldquoNeuro-toxic effects and biomarkers of lead exposure a reviewrdquoReviewson Environmental Health vol 24 no 1 pp 15ndash45 2009

[90] S J S Flora G Saxena P Gautam P Kaur and K D GillldquoResponse of lead-induced oxidative stress and alterations inbiogenic amines in different rat brain regions to combinedadministration of DMSA and MiADMSArdquo Chemico-BiologicalInteractions vol 170 no 3 pp 209ndash220 2007

[91] B Nehru and S S Kanwar ldquoN-acetylcysteine exposure onlead-induced lipid peroxidative damage and oxidative defensesystem in brain regions of ratsrdquo Biological Trace ElementResearch vol 101 no 3 pp 257ndash264 2004

[92] R Brochin S Leone D Phillips N Shepar D Zisa and AAngerio ldquoThe cellular effect of lead poisoning and its clinicalpicturerdquo Georgetown Undergraduate Journal of Health Sciencesvol 5 no 2 pp 1ndash8 2008

[93] A-M Florea J Taban E Varghese B T Alost S Moreno andD Busselberg ldquoLead (Pb2+) neurotoxicity ion-mimicry withcalcium (Ca2+) impairs synaptic transmissionrdquo Journal of Localand Global Health Science vol 4 pp 1ndash38 2013

[94] M J J Ronis T M Badger S J Shema et al ldquoEndocrine mech-anisms underlying the growth effects of developmental leadexposure in the ratrdquo Journal of Toxicology and EnvironmentalHealth vol 54 no 2 pp 101ndash120 1998

[95] P Nowak G Szczerbak D Nitka R M Kostrzewa TSitkiewicz and R Brus ldquoEffect of prenatal lead exposure onnigrostriatal neurotransmission and hydroxyl radical formation

in rat neostriatum Dopaminergic-nitrergic interactionrdquo Toxi-cology vol 246 no 1 pp 83ndash89 2008

[96] Y Ito Y Niiya H Kurita S Shima and S Sarai ldquoSerumlipid peroxide level and blood superoxide dismutase activityin workers with occupational exposure to leadrdquo InternationalArchives of Occupational and Environmental Health vol 56 no2 pp 119ndash127 1985

[97] P Ghezzi and P Di Simplicio ldquoGlutathionylation pathways indrug responserdquo Current Opinion in Pharmacology vol 7 no 4pp 398ndash403 2007

[98] V J FindlayDMTownsend T EMorris J P Fraser LHe andK D Tew ldquoA novel role for human sulfiredoxin in the reversalof glutathionylationrdquo Cancer Research vol 66 no 13 pp 6800ndash6806 2006

[99] Y Nagaoka Y Iuchi Y Ikeda and J Fujii ldquoGlutathionereductase is expressed at high levels in pancreatic islet cellsrdquoRedox Report vol 9 no 6 pp 321ndash324 2004

[100] J D Hayes J U Flanagan and I R Jowsey ldquoGlutathionetransferasesrdquo Annual Review of Pharmacology and Toxicologyvol 45 pp 51ndash88 2005

[101] A Holmgren ldquoThioredoxin and glutaredoxin systemsrdquo TheJournal of Biological Chemistry vol 264 no 24 pp 13963ndash13966 1989

[102] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica ActamdashProteins and Proteomics vol1699 no 1-2 pp 35ndash44 2004

[103] Z Krejpcio and R Wojciak ldquoEffect of doomite and thiaminesuppementation on serum tota antioxidant status and bioee-ments concentration in lead-intoxicated ratsrdquo in Trace Elementsin Man and Animals 10 pp 111ndash114 Kluwer AcademicPlenumNew York NY USA 2000

[104] H Shimada A Yasutake T Hirashima et al ldquoStrain differenceof cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 ratsrdquo Toxicology in Vitro vol 22 no2 pp 338ndash343 2008

[105] IARC International Agency for research on Cancer BerylliumCadmium Mercury and exposures in the glass manufacturingindustry vol 58 International Agency for Research on CancerMonographs on the Evaluation ofCarcinogenicRisks toHuman(IARC) Lyon France 1993

[106] M Filipic T Fatur and M Vudrag ldquoMolecular mechanismsof cadmium induced mutagenicityrdquo Human and ExperimentalToxicology vol 25 no 2 pp 67ndash77 2006

[107] M P Waalkes ldquoMetal carcinogenesisrdquo in Handbook of HeavyMetals in the Environment B Sarkar Ed pp 121ndash146 MarcelDekker 2002

[108] A Lafuente T Cabaleiro A Caride and A Romero ldquoMela-tonin and cadmium toxicityrdquo Electronic Journal of Environmen-tal Agricultural and Food Chemistry vol 7 no 8 pp 3363ndash33712008

[109] B Halliwell and J M C Gutteridge Eds Free Radicals in Biol-ogy and Medicine Uarendon Press Oxford UK 2nd edition1989

[110] E Casalino C Sblano and C Landriscina ldquoEnzyme activityalteration by cadmium administration to rats the possibility ofiron involvement in lipid peroxidationrdquo Archives of Biochem-istry and Biophysics vol 346 no 2 pp 171ndash179 1997

[111] Y Wang J Fang S S Leonard and K M K Rao ldquoCadmiuminhibits the electron transfer chain and induces reactive oxygenspeciesrdquo Free Radical Biology and Medicine vol 36 no 11 pp1434ndash1443 2004


[112] G Bertin and D Averbeck ldquoCadmium cellular effects mod-ifications of biomolecules modulation of DNA repair andgenotoxic consequences (a review)rdquo Biochimie vol 88 no 11pp 1549ndash1559 2006

[113] E Lopez C Arce M J Oset-Gasque S Canadas and M PGonzalez ldquoCadmium induces reactive oxygen species genera-tion and lipid peroxidation in cortical neurons in culturerdquo FreeRadical Biology and Medicine vol 40 no 6 pp 940ndash951 2006

[114] T W Lane and F M M Morel ldquoA biological function forcadmium in marine diatomsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no9 pp 4627ndash4631 2000

[115] T W Lane M A Saito G N George I J Pickering R CPrince and FMMMorell ldquoBiochemistry a cadmium enzymefrom a marine diatomrdquo Nature vol 435 no 7038 p 42 2005

[116] M C Henson and P J Chedrese ldquoEndocrine disruption bycadmium a common environmental toxicant with paradoxicaleffects on reproductionrdquo Experimental Biology and Medicinevol 229 no 5 pp 383ndash392 2004

[117] E K Retto deQueiroz andWWaissmann ldquoOccupational expo-sure and effects on the male reproductive systemrdquo Cadernos deSaude Publica vol 22 no 3 pp 485ndash493 2006

[118] MWaisberg P Joseph BHale andD Beyersmann ldquoMolecularand cellular mechanisms of cadmium carcinogenesisrdquo Toxicol-ogy vol 192 no 2-3 pp 95ndash117 2003

[119] JM Yang M Arnush Q Y Chen X D Wu B Pang and XZ Jiang ldquoCadmium-induced damage to primary cultures of ratLeydig cellsrdquoReproductive Toxicology vol 17 no 5 pp 553ndash5602003

[120] I Sabolic D Breljak M Skarica and C M Herak-KrambergerldquoRole of metallothionein in cadmium traffic and toxicity inkidneys and other mammalian organsrdquo BioMetals vol 23 no5 pp 897ndash926 2010

[121] M Kondoh S Araragi K Sato M Higashimoto M Takiguchiand M Sato ldquoCadmium induces apoptosis partly via caspase-9activation in HL-60 cellsrdquo Toxicology vol 170 no 1-2 pp 111ndash117 2002

[122] M Sato and M Kondoh ldquoRecent studies on metallothioneinprotection against toxicity of heavy metals and oxygen freeradicalsrdquo Tohoku Journal of Experimental Medicine vol 196 no1 pp 9ndash22 2002

[123] B I Oganjanovic S Z Pavlovic S D Maletic et al ldquoProtectiveinfluence of vitamin E on antioxidant defense system in theblood of rats treated with cadmiumrdquo Physiological Research vol52 pp 563ndash70 2003

[124] E Beytut A Yuce N N Kamiloglu and M Aksakal ldquoRoleof dietary vitamin E in cadmium induced oxidative damagein rabbits blood liver and kidneysrdquo International Journal forVitamin andNutrition Research vol 73 no 5 pp 351ndash355 2003

[125] MKarbownik EGitto A Lewinski andR J Reiter ldquoInductionof lipid peroxidation in hamster organs by the carcinogen cad-mium amelioration by melatoninrdquo Cell Biology and Toxicologyvol 17 no 1 pp 33ndash40 2001

[126] B Hultberg A Andersson and A Isaksson ldquoInteraction ofmetals and thiols in cell damage and glutathione distributionpotentiation of mercury toxicity by dithiothreitolrdquo Toxicologyvol 156 no 2-3 pp 93ndash100 2001

[127] W F Fitzgerald and T W Clarkson ldquoMercury and monometh-ylmercury present and future concernsrdquo Environmental HealthPerspectives vol 96 pp 159ndash166 1991

[128] R K Zalups ldquoMolecular interactions with mercury in thekidneyrdquo Pharmacological Reviews vol 52 no 1 pp 113ndash1432000

[129] T W Clarkson and L Magos ldquoThe toxicology of mercury andits chemical compoundsrdquoCritical Reviews in Toxicology vol 36no 8 pp 609ndash662 2006

[130] N J Langford and R E Ferner ldquoToxicity of mercuryrdquo Journalof Human Hypertension vol 13 no 10 pp 651ndash656 1999

[131] Y X Liang R K Sun Y Sun Z Q Chen and L H Li ldquoPsycho-logical effects of low-exposure to mercury vapor application ofa computer-administered neurobehavioral evaluation systemrdquoEnvironmental Research vol 60 no 2 pp 320ndash327 1993

[132] M Nordberg ldquoGeneral aspects of cadmium transport uptakeand metabolism by the kidneyrdquo Environmental Health Perspec-tives vol 54 pp 13ndash20 1984

[133] S Yee and B H Choi ldquoOxidative stress in neurotoxic effects ofmethylmercury poisoningrdquo NeuroToxicology vol 17 no 1 pp17ndash26 1996

[134] J C Clifton II ldquoMercury exposure and public healthrdquo PediatricClinics of North America vol 54 no 2 pp 237ndash269 2007

[135] O Andersen ldquoPrinciples and recent developments in chelationtreatment of metal intoxicationrdquo Chemical Reviews vol 99 no9 pp 2683ndash2710 1999

[136] M Yoshida C Watanabe M Kishimoto et al ldquoBehavioralchanges in metallothionein-null mice after the cessation oflong-term low-level exposure to mercury vaporrdquo ToxicologyLetters vol 161 no 3 pp 210ndash218 2006

[137] J P K Rooney ldquoThe role of thiols dithiols nutritional factorsand interacting ligands in the toxicology of mercuryrdquo Toxicol-ogy vol 234 no 3 pp 145ndash156 2007

[138] H Roels J P Bennart R Lauwerys J P Buchet J Malchaireand A Bernard ldquoSurveillance of workers exposed to mercuryvapour validation of a previously proposed biological thresholdlimit value for mercury concentration in urinerdquo The AmericanJournal of Industrial Medicine vol 7 no 1 pp 45ndash71 1985

[139] B Lund D M Miller and J S Woods ldquoStudies on Hg(II)-induced H

2O2formation and oxidative stress in vivo and in

vitro in rat kidney mitochondriardquo Biochemical Pharmacologyvol 45 no 10 pp 2017ndash2024 1993

[140] P L Goering B R Fisher B T Noren A Papaconstantinou JL Rojko and R J Marler ldquoMercury induces regional and cell-specific stress protein expression in rat kidneyrdquo ToxicologicalSciences vol 53 no 2 pp 447ndash457 2000

[141] J T Salonen K Seppanen K Nyyssonen et al ldquoIntake ofmercury from fish lipid peroxidation and the risk of myocar-dial infarction and coronary cardiovascular and any death inEastern Finnish menrdquo Circulation vol 91 no 3 pp 645ndash6551995

[142] E Guallar M I Sanz-Gallardo P vanrsquoT Veer et al ldquoMercuryfish oils and the risk ofmyocardial infarctionrdquoTheNewEnglandJournal of Medicine vol 347 no 22 pp 1747ndash1754 2002

[143] T Rissanen S Voutilainen K Nyyssonen T A Lakka andJ T Salonen ldquoFish oil-derived fatty acids docosahexaenoicacid and docosapentaenoic acid and the risk of acute coronaryevents the Kuopio ischaemic heart disease risk factor studyrdquoCirculation vol 102 no 22 pp 2677ndash2679 2000

[144] J S Dwayne and B T Paul ldquoMercury-induced externalizationof phosphatidylserine and caspase 3 activation in human livercarcinoma (HepG

2) cellsrdquo International Journal of Environmen-

tal Research and Public Health vol 3 no 1 pp 38ndash42 2006


[145] C D Klaassen ldquoHeavy metal and heavy metal antagonistsrdquo inGoodman and Gilmanrsquos The Pharmacological Basis of Therapeu-tics A G Gilman T W Rall A S Nies and P Taylor Eds pp1592ndash1614 Pergamon Press New York NY USA 1990

[146] S S Kety and T V Letonoff ldquoTreatment of lead poisoningwith sodium citraterdquo Proceedings of the Society for ExperimentalBiology and Medicine vol 46 no 2 pp 276ndash278 1941

[147] T D Hoover andH V Aposhian ldquoBAL increases the arsenic-74content of rabbit brainrdquo Toxicology and Applied Pharmacologyvol 70 no 1 pp 160ndash162 1983

[148] J F Risher and S N Amler ldquoMercury exposure evaluationand intervention The inappropriate use of chelating agents inthe diagnosis and treatment of putative mercury poisoningrdquoNeuroToxicology vol 26 no 4 pp 691ndash699 2005

[149] J J Chisolm Jr and D J Thomas ldquoUse of 23-dimercaptopropane-1-sulfonate in treatment of lead poisoningin childrenrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 235 no 3 pp 665ndash669 1985

[150] R K Zalups L D Parks V T Cannon and D W BarfussldquoMechanisms of action of 23-dimercaptopropane-1-sulfonateand the transport disposition and toxicity of inorganic mer-cury in isolated perfused segments of rabbit proximal tubulesrdquoMolecular Pharmacology vol 54 no 2 pp 353ndash363 1998

[151] M G Cherian E F Miles T W Clarkson and C CoxldquoEstimation of mercury burdens in rats by chelation withdimercaptopropane sulfonaterdquo Journal of Pharmacology andExperimental Therapeutics vol 245 no 2 pp 479ndash484 1988

[152] D Gonzalez-Ramirez M Zuniga-Charles A Narro-Juarezet al ldquoDMPS (23-dimercaptopropane-1-sulfonate dimaval)decreases the body burden of mercury in humans exposed tomercurous chloriderdquo Journal of Pharmacology and Experimen-tal Therapeutics vol 287 no 1 pp 8ndash12 1998

[153] H V Aposhian and M M Aposhian ldquoMeso-2 3-dimercaptosuccinic acid chemical pharmacological andtoxicological properties of an orally effective metal chelatingagentrdquo Annual Review of Pharmacology and Toxicology vol 30no 1 pp 279ndash306 1990

[154] D R Smith and A R Flegal ldquoStable isotopic tracers of leadmobilized by DMSA chelation in low leadexposed ratsrdquoToxicology and Applied Pharmacology vol 116 no 1 pp 85ndash911992

[155] S J S Flora B P Pant N Tripathi G M Kannan and DK Jaiswal ldquoDistribution of arsenic by diesters of Mesi 23dimercaptosuccinic acid during sub-chronic intoxication inratsrdquo Journal of Occupational Health vol 39 pp 119ndash123 1997

[156] J C Mayo D X Tan R M Sainz M Natarajan S Lopez-Burillo and R J Reiter ldquoProtection against oxidative proteindamage induced by metal-catalyzed reaction or alkylperoxylradicals comparative effects of melatonin and other antioxi-dantsrdquo Biochimica et Biophysica Acta vol 1620 no 1ndash3 pp 139ndash150 2003

[157] D A Cory-Slechta B Weiss and C Cox ldquoMobilization andredistribution of lead over the course of calcium disodiumethylenediamine tetraacetate chelation therapyrdquo Journal ofPharmacology andExperimentalTherapeutics vol 243 no 3 pp804ndash813 1987

[158] S J S Flora R Bhattacharya and R Vijayaraghavan ldquoCom-bined therapeutic potential of meso-23-dimercaptosuccinicacid and calcium disodium edetate on the mobilization anddistribution of lead in experimental lead intoxication in ratsrdquoToxicological Sciences vol 25 no 2 pp 233ndash240 1995

[159] I S Young and J V Woodside ldquoAntioxidants in health anddiseaserdquo Journal of Clinical Pathology vol 54 no 3 pp 176ndash1862001

[160] S K Tandon S Singh and M Dhawan ldquoPreventive effect ofvitamin E in cadmium intoxicationrdquo Biomedical and Environ-mental Sciences vol 5 no 1 pp 39ndash45 1992

[161] A Rendon-Ramirez J Cerbon-Solorzano M Maldonado-Vega M A Quintanar-Escorza and J V Calderon-SalinasldquoVitamin-E reduces the oxidative damage on 120575-aminolevulinicdehydratase induced by lead intoxication in rat erythrocytesrdquoToxicology in Vitro vol 21 no 6 pp 1121ndash1126 2007

[162] F M El-Demerdash M I Yousef F S Kedwany and H HBaghdadi ldquoCadmium-induced changes in lipid peroxidationblood hematology biochemical parameters and semen qualityof male rats protective role of vitamin E and 120573-carotenerdquo Foodand Chemical Toxicology vol 42 no 10 pp 1563ndash1571 2004

[163] D Quig ldquoCysteine metabolism and metal toxicityrdquo AlternativeMedicine Review vol 3 no 4 pp 262ndash270 1998

[164] R Tirouvanziam C K Conrad T Bottiglieri L A Herzenbergand R BMoss ldquoHigh-dose oralN-acetylcysteine a glutathioneprodrug modulates inflammation in cystic fibrosisrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 103 no 12 pp 4628ndash4633 2006

[165] Z A Shaikh K Zaman W Tang and T Vu ldquoTreatment ofchronic cadmium nephrotoxicity by N-acetyl cysteinerdquo Toxicol-ogy Letters vol 104 no 1-2 pp 137ndash142 1999

[166] J Bustamante J K Lodge L Marcocci H J Tritschler LPacker and B H Rihn ldquo120572-lipoic acid in liver metabolism anddiseaserdquo Free Radical Biology and Medicine vol 24 no 6 pp1023ndash1039 1998

[167] R Sumathi G Baskaran and P Varalakshmi ldquoEffect of DL 120572-lipoic acid on tissue redox state in acute cadmium-challengedtissuesrdquoThe Journal of Nutritional Biochemistry vol 7 no 2 pp85ndash92 1996

[168] L Muller ldquoProtective effects of DL-120572-lipoic acid on cadmium-induced deterioration of rat hepatocytesrdquoToxicology vol 58 no2 pp 175ndash185 1989

[169] J J Garcıa R J Reiter J M Guerrero et al ldquoMelatonin preventschanges inmicrosomal membrane fluidity during induced lipidperoxidationrdquo The FEBS Letters vol 408 no 3 pp 297ndash3001997

[170] A I Othman S Al Sharawy and M A El-Missiry ldquoRoleof melatonin in ameliorating lead induced haematotoxicityrdquoPharmacological Research vol 50 no 3 pp 301ndash307 2004

[171] G H El-Sokkary G H Abdel-Rahman and E S KamelldquoMelatonin protects against lead-induced hepatic and renaltoxicity in male ratsrdquo Toxicology vol 213 no 1-2 pp 25ndash332005

[172] J Limson T Nyokong and S Daya ldquoThe interaction of mela-tonin and its precursors with aluminium cadmium copperiron lead and zinc an adsorptive voltammetric studyrdquo Journalof Pineal Research vol 24 no 1 pp 15ndash21 1998

[173] M Kotler C Rodriguez R M Sainz I Antolin and A MPelaez ldquoMelatonin increases gene expression for antioxidantenzymes in rat brain cortexrdquo Journal of Pineal Research vol 24no 2 pp 83ndash89 1998

[174] D Melchiorri R J Reiter A M Attia M Hara A Burgosand G Nistico ldquoPotent protective effect of melatonin on in vivoparaquat-induced oxidative damage in ratsrdquo Life Sciences vol56 no 2 pp 83ndash89 1995


[175] R J Reiter D-X Tan J Cabrera et al ldquoThe oxidantantioxidantnetwork role of melatoninrdquo Biological Signals and Receptorsvol 8 no 1-2 pp 56ndash63 1999

[176] V Srinivasan G JMMaestroni D P Cardinali A I EsquifinoS R Pandi Perumal and S C Miller ldquoMelatonin immunefunction and agingrdquo Immunity and Ageing vol 2 article 172005

[177] R J Reiter D Tan and S Burkhardt ldquoReactive oxygen andnitrogen species and cellular and organismal decline ameliora-tion with melatoninrdquo Mechanisms of Ageing and Developmentvol 123 no 8 pp 1007ndash1019 2002

[178] C Pieri M Marra F Moroni R Recchioni and F MarchesellildquoMelatonin a peroxyl radical scavenger more effective thanvitamin Erdquo Life Sciences vol 55 no 15 pp PL271ndashPL276 1994

[179] R J Reiter ldquoMelatonin clinical relevancerdquo Best Practice andResearch Clinical Endocrinology andMetabolism vol 2 pp 273ndash285 2003

[180] S J S Flora ldquoInfluence of simultaneous supplementation ofzinc and copper during chelation of lead in ratsrdquo Human andExperimental Toxicology vol 10 no 5 pp 331ndash336 1991

[181] G J S Flora P K Seth and S J S Flora ldquoRecoveries in leadinduced alterations in rat brain biogenic amines levels followingcombined chelation therapy with meso 23-dimercaptosuccinicacid and calcium disodium versenaterdquo Biogenic Amines vol 13no 2 pp 79ndash90 1997

[182] S Bhadauria and S J S Flora ldquoResponse of arsenic-inducedoxidative stress DNA damage and metal imbalance to com-bined administration of DMSA and monoisoamyl-DMSA dur-ing chronic arsenic poisoning in ratsrdquo Cell Biology and Toxicol-ogy vol 23 no 2 pp 91ndash104 2007

[183] S J S Flora S C Pant and A S Sachan ldquoMobilization anddistribution of lead over the course of combined treatmentwith thiamine and meso 23-dimercaptosuccinic acid or 23-dimercaptopropane sulphonate in ratsrdquo Clinical Chemistry andEnzymology Communications vol 6 no 4 pp 207ndash216 1994

[184] D Mishra and S J S Flora ldquoQuercetin administration duringchelation therapy protects arsenic-induced oxidative stress inmicerdquo Biological Trace Element Research vol 122 no 2 pp 137ndash147 2008

[185] R Lauwerys H Roels J P Buchet A A Bernard L Verhoevenand J Konings ldquoThe influence of orally-administered vitaminCor zinc on the absorption of and the biological response to leadrdquoJournal of Occupational Medicine vol 25 no 9 pp 668ndash6781983

[186] S J S Flora A Mehta and R Gupta ldquoPrevention of arsenic-induced hepatic apoptosis by concomitant administration ofgarlic extracts inmicerdquoChemico-Biological Interactions vol 177no 3 pp 227ndash233 2009

[187] S J S Flora and V Pachauri ldquoChelation in metal intoxicationrdquoInternational Journal of Environmental Research and PublicHealth vol 7 no 7 pp 2745ndash2788 2010

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


Ions

Hydrogenperoxide (H2O2)

Hypochloriteion (OCl minus)

ROS contain nonradicals

MoleculesH

H

H

H

Reactive oxygen species (ROS)

minus minus

Superoxideanion (O 2

∙minus)

OO

OOO

OOO

Clradical (HO 2

∙)

Hydroxyl

Hydroperoxylradical (OH ∙)

and radicals

Figure 1 Reactive oxygen species (ROS) existing in radicals andnonradicals forms

nature and severity of toxicity vary with the heavy metalinvolved its exposure level chemical and valence states(inorganic versus organic) mode of exposure (acute versuschronic) and the age of the individual Children with theirdeveloping nervous systems are particularly vulnerable toheavy metal intoxication (especially lead)

The heavy metals induced toxicity has been extensivelystudied and reported by various workers They have demon-strated that the exposure of an animal to excess concen-trations of these elements may augment production of freeradicals which may cause oxidative stress [2ndash5] In factgeneration of oxidative stress has been considered as oneof the major mechanisms behind heavy metal toxicity Theheavymetals have potential towards production of the highlyreactive chemical entities such as free radicals having theability to cause lipid peroxidation DNA damage oxidationof sulfhydryl groups of proteins depletion of protein andseveral other effects [3] The heavy metals have been foundto generate reactive oxygen species (ROS) which in turnresults in their toxic effects in the form of hepatotoxicity andneurotoxicity as well as nephrotoxicity in both animals andhumans [2 4] Some of the reactive oxygen species are shownin Figure 1Their few characteristic properties and impact oncellular systems are summarized in Table 1

This review summarizes an updated account of availableinformation on heavymetals induced imbalance in the redoxsystems in the body and their clinical and pathophysiologicalimplications as well as use of certain natural and syntheticproducts to mitigate their toxicity It illustrates toxic effects ofonly four key heavy metals such as arsenic lead cadmiumandmercury which are ubiquitous in air andwater pollutantsthat continue to threaten the quality of public health aroundthe world These elements are associated with many adversehealth effects generated through oxidative damage and dis-ease processes [5]

2 Arsenic

Arsenic is particularly difficult to characterize as a singleelement because its chemistry is really complex Arsenicoccurs in three oxidation states trivalent arsenite (As (III))

Table 1 Brief description of some reactive oxygen species (ROS)

Oxidant Description

∙O2

minussuperoxideanion

One-electron reduction state of O2 formedin many autoxidation reactions and by theelectron transport chain Rather unreactivebut can release Fe2+ from iron-sulfurproteins and ferritin Undergoesdismutation to form H2O2 spontaneously orby enzymatic catalysis and is a precursor formetal-catalyzed ∙OH formation

H2O2 hydrogenperoxide

Two-electron reduction state formed bydismutation of ∙O

2

minus or by direct reductionof O2 Lipid soluble and thus able to diffuseacross membranes

∙OH hydroxylradical

Three-electron reduction state formed byFenton reaction and decomposition ofperoxynitrite Extremely reactive and willattack most cellular components

ROOH organichydroperoxide

Formed by radical reactions with cellularcomponents such as lipids and nucleobases

RO∙ alkoxyand ROO∙peroxy radicals

Oxygen centred organic radicals Lipidforms participate in reactions Produced inthe presence of oxygen by radical additionto double bonds or hydrogen abstraction

HOClhypochlorousacid

Formed from H2O2 by myeloperoxidaseLipid soluble and highly reactive Willreadily oxidize protein constituentsincluding thiol groups amino groups andmethionine

ONOOminusperoxynitrite

Formed in a rapid reaction between ∙O2

minus

and NO∙ Lipid soluble and similar inreactivity to hypochlorous acid Protonationforms peroxynitrous acid which canundergo homolytic cleavage to formhydroxyl radical and nitrogen dioxide

pentavalent arsenate (As (V)) and elemental Arsenite is tentimes more toxic than arsenate elemental arsenic is non-toxic Arsenic also exists in three chemical forms organicinorganic and arsine gas with organic arsenic having littletoxicity whereas inorganic arsenic and arsine gas are toxicIt is widely distributed in nature and utilizes its three mostcommon oxidation numbers (+5 +3 and ndash3) to form chemi-cal complexes in body A summary of environmental sourcesof arsenic as well as their potential health effects is men-tioned in the National Research Council report on arsenicin drinking water Most major US drinking water suppliescontain levels lower than 5 120583gL It has been estimated thatabout 350000 thousand peoplemight drinkwater containingmore than 50120583gL [7] Exposure to arsenic primarily occursby ingestion but inhalation and absorption through the skinare possible Arsenic occurs naturally in seafood as nontoxicorganic compounds such as arsenobetaine which can causeelevated urine arsenic levels The lethal dose of inorganicarsenic has been estimated to be 06mgkg

About 80ndash90 of a single dose of arsenite As (III)or arsenate As (V) has been shown to be absorbed fromthe gastrointestinal (GI) tract of humans and experimental






Diffusion





MEKK 3 4MEKK 2 3 4

As5+

As5+

As3+

As3+

(JNK MAP4K MAP3K)






2∙












50= 35 120583M after











4 Lead














3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






Diffusion





MEKK 3 4MEKK 2 3 4

As5+

As5+

As3+

As3+

(JNK MAP4K MAP3K)






2∙












50= 35 120583M after











4 Lead














3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of









50= 35 120583M after











4 Lead














3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of








4 Lead














3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of












3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



3

minus andCO3

















Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of










Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table2Th

ephysic

alchemicaland

clinicalpropertieso

fheavy

metalsincludedin

ther

eview


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Absorptio

n

GIino

rganictriv

alentand


also

boun

das

tri-andpentavalent

gt90inh

alation

uptake

isdepend

entu

ponparticlesiz

e

Skinalkyllead

compo

undsbecause

oflip

idsolubility(m

ethyland

tetraethyl

lead)inhalation

upto

90depend

ing

upon

particlesiz

eGIadults5to

10

child

ren40

Inhalation10

to40

GI15to

5

GIinorganics

altsmay

beabsorbed

and

may

beconvertedto

organicm

ercury

intheg

utby

bacteriainh

alation

elem

ental

Hgcompletely

absorbed

Distrib

ution

Accumulates

inlung

heartkidney

liverm

uscle

and

neuraltissue

concentrates

inskinn

ails

andhair

Initiallycarriedin

redcells

and

distrib

uted

tosofttissues

(kidneyand

liver)bo

neteethand

hairmostly

asa

phosph

ates

alt

Initiallybo

undto

albu

min

andbloo

dcells

subsequentlyto

metallothionene

inliver

andkidn

ey

Elem

entalH

g(vapor)crosses

mem

branes

well

andrapidlymoves

from

lung

toCN

SOrganicsalts

(lipidsoluble)aree

venly

distrib

utedintestin

al(in

tracellular)-fe

cal

elim

ination

Inorganics

altsconcentrate

inbloo

dplasmaandkidn

ey(renal

elim

ination)

Half-life

7to

10h

Bloo

d30ndash6

0daysbon

e20ndash30years

10to

20years

60to

70days

Sourceso

fexp

osure

GIwellw

aterfoo

dEn

vironm

ental

by-produ

ctof

smeltingoreas

Gain

semicon


pesticidesinh

alation

fumes

and

dustfro

msm

elting

GIpaintpo

tterym

oonshineinh

alation

metalfumes


gasolin

e

GIpigm

ents

polishes

antiq

uetoys

environm

ental

Electro

plating

galvanization

plastic

sbatte

riesinhalation

indu

stria

lmetalfumes

tobacco

Environm

entalelectro

nics

andplastic

indu

stryseedfung

icidetreatment

dentistry

Mechanism

oftoxicity

Mem

branesprotein

damageo

fcapillary

endo

thelium

increased

vascular

perm

eabilityleadingto

vasodilatio

nandvascular

collapse

inhibitio

nof

sulfh

ydrylgroup

containing

enzymesinh

ibition

ofanaerobica

ndoxidative

phosph

orylation(sub

stitutesfor

inorganicp

hosphatein

synthesis

ofhigh

-energyph

osph

ates)

Inhibitio

nof

hemeb

iosynthesishem

eis

thee

ssentia

lstructuralcom

ponent

ofhemoglobin

myoglob

inand

cytochromes

Bind

stosulfh

ydrylgroup

s(-SH

grou

ps)o

fproteins

Inhalation

lung

local

irritatio

nandinhibitio

nof

alph

a 1-antitrypsin

associated

with

emph

ysem

aoralkidney

proxim

altubu

larinjury

(proteinuria)a

ssociated

with

beta

2-acroglob

ulin

Diss

ociatio

nof

salts

precipitatesp

roteins

anddestroys

mucosalmem

branes

necrosisof

proxim

altubu

lare

pithelium

inhibitio

nof

sulfh

ydryl(-SH)g

roup

containing

enzymes

Diagn

osis

Historyof

expo

sureblood

and


fingernail(chronic)

Historyof

expo

surew

holebloo

dlevel

(childrengt25

ugdLandadults

gt50

ugdL)protopo

rphyrin

levelsin

RBCsgt40


Historyof

expo

surew

hole

bloo

dCdlevelgt

80120583gdL

Historyof

expo

sureblood

mercury


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table2Con

tinued


ical

prop

ertie

sHeavy

metals

Arsenic(A

s)Lead

(Pb)

Cadm

ium

(Cd)

Mercury

(Hg)

Symptom

s


sloug

hing

hypovolem

icshock

feverGId

iscom

fortpain

anorexia

chronicw

eakn

essGI

hepatomegaly(ja

undicegt

cirrho

sis)melanosis

arrhythm

ias

perip

heraln

europathyperip

heral

vascular

disease(blackfoo

tdise

ase)

carcinogenicity

epidemiologic

evidenceliver

angiosarcomaa

ndskin

andlung

cancer

Acutenauseavom

iting

thirst

diarrheacon

stipation

abdo

minalpain

hemoglobinu

riaand

oligurialeadingto

hypo

volemicshock

ChronicGIlead

colic

(nauseavomiting

abdo

minalpain)

NMJlead

palsy

(fatig

uew

ristd

rop)

CNSlead

enceph

alop

athy

(headache

vertigoirr

itatio

ninsomniaCN

Sedem

a)

Acuteoralvom

iting

diarrheaabd

ominal

cram

psinh

alation

chest


diarrheapulmon

ary

edem

aCh

ronicoral

neph

rotoxicity

inhalatio

nem

physem

a-lik

esynd

romea

ndneph

rotoxicity

Acute(a)ino

rganicsalts

degradationof

mucosa-GIp

ain

vomiting

diuresis

anem

iahypovolem

icshockrenal

toxicity(b)

organicC

NSinvolvem

ent

visio

ndepressio

nirr

itability

blushing

intentio

ntre

morsinsomnia

fatig

uediuresis

Ch

ronicCN

Ssymptom

ssim

ilartoacute

organicp

oisoning

with

ging

ivitis


Treatm

ents

Removalfro

mexpo

sure

Acutesupp

ortiv

etherapyfluid

electro

lytereplacem

entbloo

dpressure

supp

ort(do

pamine)


odialysis

arsin

egas

(AsH

3)actsas

ahemolyticagentw

ithsecond

aryto

renalfailureSup

portivetherapy

transfu

sion

chelatorsh

aven

otbeen

show

nto

bebeneficial

Removalfro

mexpo

suretreatmentw

ithchelatorslikeC

aNa 2ED

TAB

AL

dimercaprolD

-penicillam

ine

Removalfro

mexpo

sure


CaNa 2ED

TAB

ALbu

tBA

L-Cdcomplex

isextre

mely

toxicso

itisno

tused

Removalfro

mexpo

sureH

gandHgsalts

gt4120583

gdL

23-dim

ercaptop

ropano

l(BA

L)

120573120573

-dim


mosteffectiveisN

-acetyl-120573

120573-dim

ethyl

cyste

ine(N-acetyl-p

enicillam

ine)m

ethyl

Hg-supp

ortiv

etreatment(no

nabsorbable

thiolresinsc

anbe

givenorallyto

redu

cemethylH

glevelingut)

Minim

alperm

issibledo

sefor

human

s10ndash5

0120583gk

gminus1(EPA

reference)

5120583gk


reference)

05ndash1120583

gkgminus

1 dayminus1

(EPA

reference)

01ndash2120583

gkgminus

1 dayminus1(EPA

reference)


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of








6 Cadmium




















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of















8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



8 Mercury









































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


































12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


























12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of













12 DMPS








2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





2EDTA)


2EDTA is a deriva-






2EDTA as a suitable


15 Vitamins C and E




16 120573-Carotene







19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






19 Melatonin



2




2O2from rat







21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





21 Conclusion





References














































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

































































































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

























































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of
























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



















Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Documents

Review Article Biomedical Implications of Heavy …downloads.hindawi.com/journals/bmri/2014/640754.pdfReview Article Biomedical Implications of Heavy Metals ... It is well known that