AcuteandchronicarsenictoxicityRNRatnaikePostgradMedJArsenictoxicityisa - PDF document

AcuteandchronicarsenictoxicityRNRatnaikePostgradMedJArsenictoxicityisaglobalhealthproblemaffectingmanymillionsofpeople.Contaminationiscausedbyarsenicfromnaturalgeologicalsourcesleachingintoaquifers,contaminatingdrinkingwaterandmayalsooccurfromminingandotherindustrialprocesses.Arsenicispresentasacontaminantinmanytraditionalremedies.Arsenictrioxideisnowusedtotreatacutepromyelocyticleukaemia.Absorptionoccurspredominantlyfromingestionfromthesmallintestine,thoughminimalabsorptionoccursfromskincontactandinhalation.Arsenicexertsitstoxicitybyinactivatingupto200enzymes,especiallythoseinvolvedincellularenergypathwaysandDNAsynthesisandrepair.Acutearsenicpoisoningisassociatedinitiallywithnausea,vomiting,abdominalpain,andseverediarrhoea.Encephalopathyandperipheralneuropathyarereported.Chronicarsenictoxicityresultsinmultisystemdisease.Arsenicisawelldocumentedhumancarcinogenaffectingnumerousorgans.Therearenoevidencebasedtreatmentregimenstotreatchronicarsenicpoisoningbutantioxidantshavebeenadvocated,thoughbenefitisnotproven.Thefocusofmanagementistoreducearsenicingestionfromdrinkingwaterandthereisincreasingemphasisonusingalternativesuppliesofwater.rsenicisoneofthemosttoxicmetalsderivedfromthenaturalenvironment.Themajorcauseofhumanarsenictoxicityisfromcontaminationofdrinkingwaterfromnaturalgeologicalsourcesratherthanfrommining,smelting,oragriculturalsources(pesticidesorfertilisers).Manyindustrialisedandlessindustr-ialisedcountrieshavedrinkingwatercontami-natedwitharsenic.TheproblemisofmajorconcernintheUSA—forexample,thearseniccontentofdrinkingwaterfrompublicandprivatesourcesinMillardCountyrangesfrom14partsperbillion(ppb)to166ppb.TheEnvironmentProtectionAgencyloweredthepermissiblelevelofarsenicindrinkingwaterintheUSAin2001from50ppbto10ppb.Prolongedingestionofwatercontaminatedwitharsenicmayresultinthemanifestationsoftoxicityinpracticallyallsystemsofthebodyassubsequentlydiscussed.Themostseriousconcernisthepotentialofarsenictoactasacarcinogen.ThetwoworstaffectedareasintheworldareBangladeshandWestBengal,India.In42districtsinsouthernBangladeshandinnineadjacentdistrictsinWestBengal,79.9millionand42.7millionpeoplerespectivelyareexposedtogroundwaterarsenicconcentrationsthatareabovetheWorldHealthOrganisationmaximumpermissiblelimitof50Inboththeseareas,thesourceofarsenicisgeologicalinorigin,contaminatingaquiferswhichprovidewaterforoveronemilliontubewells.InWestBengalthearsenicconcentrationinsometubewellsisashighas3400ThemechanismofarsenicaccumulationintheBengalDeltaPlainisthoughttohaveoccurredduringthelateQuaternaryage(Holoceneage)witharsenic-containingalluvialsedimentsde-positedbytheGanges,Brahmaputra,Meghna,andothersmallerriversthatowacrosstheBen-galDeltaPlainintotheBayofBengal.IntheBengalDeltaPlain,thearsenicisadsorbedasarsenicoxyanionsontooxyhydroxidesofiron,aluminium,andmanganeseandthenmobilisedinthealluvialaquiferswhere,duetothereducingenvironment,theoxyhydroxidesaredissolvedbybiogeochemicalprocesses,releasingthearsenicintothegroundwater.Overthecenturies,arsenichasbeenusedforavarietyofpurposes.Arsenicwasaconstituentincosmetics,andusedmoreextensivelythanatpresentinagriculturetoprotectcropsfrompests.Arsenicascopperacetoarsenitewasapigmentinpaints,thebestknownbeing“Parisgreen”.Beforeelectricitywasusedforillumination,hydrogenliberatedfromcoalresandfromgasforlightingcombinedwitharsenicintheParisgreenusedinwallpapertoformarsine,atoxicgas.AfungusScopulariopsisbreviculispresentindampwallpaperalsometabolisedthearsenicinParisgreentoarsine.Inindustry,arsenicisusedtomanufacturepaints,fungicides,insecticides,pesticides,herbi-cides,woodpreservatives,andcottondesiccants.Asitisanessentialtraceelementforsomeanimals,arsenicisanadditiveinanimalfeed.Galliumarse-nideoraluminiumgalliumarsenidecrystalsarecomponentsofsemiconductors,lightemittingdiodes,lasers,andavarietyoftransistors.Arsenicisapopularmurderweapon.ManyarseniccompoundsresemblewhitesugarandthisapparentinnocuousnessisenhancedbybeingtastelessandodourlessandwaspublicisedbyFrankCapra’slmArsenicandOldLace,inwhichtwoelderlyladiesusearsenicinelderberrywinetomurdertheirmalesuitors.AIF,apoptosisinducingfactor;,/AsV,arsenate;As,/AsIII,arsenite;ppb,partsperbillion;ppm,partspermillionCorrespondenceto:ProfessorRanjitNRatnaike,QueenElizabethHospital,Woodville,SouthAustralia5011,Australia;14November2002Accepted31March2003 HISTORICALTHERAPEUTICUSESOFARSENICArsenicwasusedasahealingagentafterGreekphysicianssuchasHippocratesandGalenpopulariseditsuse.Arseniccom-poundsbecameavailableassolutions,tablets,pastes,andininjectableforms.Fowler’ssolution,a1%arsenictrioxideprepa-ration,waswidelyusedduringthe19thcentury.Asrecentlyas1958,theBritishPharmaceuticalandTherapeuticProductsbookeditedbyMartindale,listedtheindicationsforFowler’ssolutionas:leukaemia,skinconditions(psoriasis,dermatitisherpetiformis,andeczema),stomatitisandgingivitisininfants,andVincent’sangina.Fowler’ssolutionwasalsoprescribedasahealthtonic.ChronicarsenicintoxicationfromthelongtermuseofFowler’ssolutioncausedhaemangiosarcoma,angiosar-comaoftheliver,1112andnasopharyngealcarcinoma.ArsenicwastheprimarytreatmentforsyphilisuntilWorldWarII.Arsphenamine(neoarsphenamine),alightyellowcompoundcontaining30%arsenicwasusedintravenouslytotreatsyphilis,yaws,andsomeprotozoaninfections.CURRENTTHERAPEUTICUSESOFARSENICArsenictrioxide(As)isnowwidelyusedtoinduceremissioninpatientswithacutepromyelocyticleukaemia,basedonitsmechanismasaninducerofapoptosis(programmedcelldeath).Arsenicinducesapoptosisbyreleasinganapoptosis-inducingfactor(AIF)fromthemitochondrialintermembranespacefromwhereittranslocatestothecellnucleus.AIFtheneffectsapoptosis,resultinginalterednuclearbiochemistry,chromatincondensation,DNAfragmentation,andcelldeath.AIFhasbeenisolatedandclonedandisaavoproteinwithamolecularweightof57000.Arseniccontinuestobeanessentialconstituentofmanynon-westerntraditionalmedicineproducts.SomeChinesetraditionalmedicationscontain(arsenicsulphide)andareavailableaspills,tablets,andotherpreparations.Theyareusedforpsoriasis,syphilis,asthma,rheumatism,haemor-rhoids,coughandpruritus,andarealsoprescribedasahealthtonic,ananalgesic,anti-inammatoryagent,andasatreatmentforsomemalignanttumours.InIndia,herbalmedicinescontainingarsenicareusedinsomehomoeopathicpreparationsandhaematologicalmalignancies.InKoreaarsenicisprescribedinherbalmedicineforhaemorrhoids.Howeverratherthananintendedingredient,arsenicismoreoftenacontaminant,sometimeswithmercuryand222728TheDepartmentofHealthServicesofCaliforniascreened251productsinretailherbalstoresanddetectedarsenicin36products(14%)inconcentrationsfrom20.4to114000partspermillion(ppm)withameanof145.53ppmandthemedian180.5ppm.AstudyinSingaporeidentied17patientsduringaveyearperiodwithcutaneouslesionsrelatedtochronicarsenictoxicity,andin14(82%)patientstoxicitywasduetoarsenicfromChineseproprietarymedicineswhiletheotherthreeconsumedwellwatercontaminatedwitharsenic.CHEMISTRYANDTOXICITYArsenicoccursintwooxidationstates:atrivalentform,arsen-ite(As;AsIII)andapentavalentform,arsenate(As;AsV).AsIIIis60timesmoretoxicthanAsV.Organicarsenicisnon-toxicwhereasinorganicarsenicistoxic.Arsenictoxicityinactivatesupto200enzymes,mostnotablythoseinvolvedincellularenergypathwaysandDNAreplicationandrepair,andissubstitutedforphosphateinhighenergycompoundssuchasATP.Unboundarsenicalsoexertsitstoxicitybygeneratingreac-tiveoxygenintermediatesduringtheirredoxcyclingandmetabolicactivationprocessesthatcauselipidperoxidationandDNAdamage.AsIII,especially,bindsthiolorsulfhydrylgroupsintissueproteinsoftheliver,lungs,kidney,spleen,gastrointestinalmucosa,andkeratin-richtissues(skin,hair,andnails).ManyothertoxiceffectsduetoarsenicarebeingdeterminedandaredetailedbyAbernathyetalin1999.ARSENICEXPOSUREArsenicexposureoccursfrominhalation,absorptionthroughtheskinand,primarily,byingestionof,forexample,contami-nateddrinkingwater.Arsenicinfoodoccursasrelativelynon-toxicorganiccompounds(arsenobentaineandarseno-choline).Seafood,sh,andalgaearetherichestorganicsources.Theseorganiccompoundscauseraisedarseniclevelsinbloodbutarerapidlyexcretedunchangedinurine.3233Arsenicintakeishigherfromsolidfoodsthanfromliquidsincludingdrinkingwater.3435Organicandinorganicarseniccompoundsmayentertheplantfoodchainfromagriculturalproductsorfromsoilirrigatedwitharseniccontaminatedwater.Themajorsiteofabsorptionisthesmallintestinebyanelec-trogenicprocessinvolvingaproton(H)gradient.optimalpHforarsenicabsorptionis5.0,thoughinthemilieuofthesmallbowelthepHisapproximately7.0duetopancre-aticbicarbonatesecretion.Theabsorbedarsenicundergoeshepaticbiomethylationtoformmonomethylarsonicacidanddimethylarsinicacidthatarelesstoxicbutnotcompletelyinnocuous.4041About50%oftheingesteddosemaybeeliminatedintheurineinthreetovedays.Dimethylarsinicacidisthedominanturinarymetabolite(60%–70%)comparedwithmonomethylarsonicAsmallamountofinorganicarsenicisalsoexcretedunchanged.Afteracutepoisoningelectrothermalatomicabsorptionspectrometrystudiesshowthatthehighestconcentrationofarsenicisinthekidneysandliver.Inchronicarsenicingestion,arsenicaccumulatesintheliver,kidneys,heart,andlungsandsmalleramountsinthemuscles,nervoussystem,gastrointestinaltract,andspleen.Thoughmostarsenicisclearedfromthesesites,residualamountsremaininthekeratin-richtissues,nails,hair,andskin.Afterabouttwoweeksofingestion,arsenicisdepositedinthehairandnails.CLINICALFEATURESAcutepoisoningMostcasesofacutearsenicpoisoningoccurfromaccidentalingestionofinsecticidesorpesticidesandlesscommonlyfromattemptedsuicide.Smallamounts(mg)resultinvomitinganddiarrhoeabutresolvein12hoursandtreatmentisreportednottobenecessary.Thelethaldoseofarsenicinacutepoisoningrangesfrom100mgto300mg.TheRiskAssessmentInformationSystemdatabasestates“Theacutelethaldoseofinorganicarsenictohumanshasbeenestimatedtobeabout0.6mg/kg/day”.A23yearoldmalewhoingested8gofarsenicsurvivedforeightdays.Astudentwhoconsumed30gofarsenicsoughthelpafter15hoursandsur-vived48hoursbutdieddespitegastriclavageandtreatmentwithBritishanti-lewisite(anarsenicantidote)andhaemodialysis.Dependingonthequantityconsumed,deathusuallyoccurswithin24hourstofourdays.Theclinicalfeaturesinitiallyinvariablyrelatetothegastro-intestinalsystemandarenausea,vomiting,colickyabdominalBox1:IndustrialsourcesAgriculturalpesticidesandherbicides.Paints,fungicides,insecticides,woodpreservatives,andcottondesiccants.Manufactureofsemiconductors,lightemittingdiodes,andcomponentsoflasersandmicrowavecircuits. pain,andprofusewaterydiarrhoea.Theabdominalpainmaybesevereandmimicanacuteabdomen.Excessivesalivationoccursandmaybethepresentingcomplaintintheabsenceofothergastrointestinalsymptoms.Otherclinicalfeaturesareacutepsychosis,adiffuseskinrash,toxiccardiomyopathy,4752andseizures.Diarrhoeaattributedtoincreasedpermeabilityofthebloodvesselsisadominantfeature.Thevoluminouswaterystoolsaredescribedas“choleroiddiarrhoea”.Incholerathestoolsaredescribedas“ricewater”,butinacutearsenicpoisoning,becauseofbloodinthegastrointestinaltract,theterm“bloodyricewater”diarrhoeaisused.Thecauseofdeathismassiveuidlossduetosecretionfromthegastrointestinaltracteventuatinginseveredehydration,reducedcirculatingbloodvolume,andconsequentcirculatorycollapse.Onpostmortemexaminationoesophagitis,gastritis,andhepaticsteatosisarereported.Haematologicalabnormalitiesreportedarehaemaglobinu-ria,intravascularcoagulation,bonemarrowdepression,severepancytopenia,andnormocyticnormochromicanaemiaandbasophilicstippling.Renalfailurewasreportedinfourofeightsailorsexposedtoarsine.RespiratoryfailureandpulmonaryoedemaarecommonfeaturesofacuteThemostfrequentneurologicalmanifestationisperipheralneuropathythatmaylastforaslongastwoyears.475556peripheralneuropathymayleadtorapid,severeascendingweakness,similartoGuillain-Barrésyndrome,requiringmechanicalventilation.Encephalopathyisacommonmani-festationandthepossibilityofarsenictoxicitymustbeconsiderediftheaetiologyofencephalopathyisuncertain.Encephalopathyhasoccurredafterintravenousadministra-tionofarsphenamines.Thebasisfortheencephalopathyisthoughttobeduetohaemorrhage.Metabolicchangeswithacutearsenicpoisoningarereported.Acidosishasoccurredinasinglepatienthypoglycaemiaandhypocalcaemiaincattle.Inacutepoison-ingthebestindicatorofrecentingestion(1–2days)isurinaryarsenicconcentration.ChronicpoisoningLongtermarsenictoxicityleadstomultisystemdiseaseandthemostseriousconsequenceismalignancy.Theclinicalfea-turesofarsenictoxicityvarybetweenindividuals,populationgroups,andgeographicareas.Itisunclearwhatfactorsdeter-minetheoccurrenceofaparticularclinicalmanifestationorwhichbodysystemistargeted.Thusinpersonsexposedtochronicarsenicpoisoning,awiderangeofclinicalfeaturesarecommon.Theonsetisinsidiouswithnon-specicsymptomsofabdominalpain,diarrhoea,andsorethroat.Numerousskinchangesoccurwithlongtermexposure.matologicalchangesareacommonfeatureandtheinitialclinicaldiagnosisisoftenbasedonhyperpigmentation,palmarandsolarkeratosis.Thekeratosismayappearasauni-formthickeningorasdiscretenodules.961Itisemphasisedthatbothpalmarsolarkeratosisareasignicantdiagnosticcriterion.Hyperpigmentationoccursasdiffusedarkbrownspots,orlessdiscretediffusedarkeningoftheskin,orhasacharacteristic“raindrop”appearance.Arsenicassociatedskincancer,Bowen’sdisease,isanuncommonmanifestationinAsiansandmaybeduetothehighskinmelanincontentandincreasedexposuretoultravioletradiation.Arsenicmaycauseabasalcellcarcinomainanon-melaninpigmentedThelatentperiodafterexposuremaybeaslongas60yearsandhasbeenreportedinpatientstreatedwithFowler’ssolution,insheepdipworkers,invineyardworkersusingarsenicalpesticides,andfromdrinkingcontaminatedwine.Anothermanifestationduetoarsenicdepositioninkeratin-richareasareprominenttransversewhitelinesinthenger-nailsandtoenailscalledMee’slines.LargepopulationbasedstudiesfromWestBengalinIndiashowarelationshipbetweenarsenicconcentrationintubewellwater,doseperbodyweight,andhyperpigmentationandkeratosis,andthatpersonswithapoornutritionalstatusweremoresusceptible.HoweverthestudybySmithetalreportsthatarsenicinducedskinlesionsoccuramongAtacamenopeopleinnorthernChile,despiteagoodnutritionalstatus.subjectsinChiuChiuvillagewerefromanarea“famous”foritscultivationofcarrotsandothervegetables.Thearseniccontentofthefoodconsumedwasnotmeasuredtodetermineifarsenicinthefoodchainperhaps“nullied”thenutritionalbenetsofthefoodsconsumed.GastrointestinalsystemThoughdiarrhoeaisamajorandearlyonsetsymptominacutearsenicpoisoning,inchronictoxicitydiarrhoeaoccursinrecurrentboutsandmaybeassociatedwithvomiting.Suspicionofarsenicingestionshouldbearousedifothermanifestationssuchasskinchangesandaneuropathyarealsopresent.In248patientswithevidenceofchronicarsenictoxicityfromWestBengal,Indiawhoconsumedarsenic-contaminateddrinkingwaterforoneto15years,hepatome-galyoccurredin76.6%,andofthe69whowerebiopsied,63(91.3%)showednon-cirrhoticportalbrosis.Inanotherstudy,arsenicwasconsideredtheaetiologicalagentinveof42patientswithincompleteseptalcirrhosis,aninactiveformofmacronodularcirrhosis,characterisedbyslender,incom-pleteseptathatdemarcateinconspicuousnodules,andanunusuallyhighincidenceofvaricealbleeding.CardiovascularsystemIncreasedriskofcardiovasculardiseaseisreportedinsmelterworkersduetoarsenicexposure.InastudyinMillardBox2:AcutearsenicpoisoningClinicalfeaturesmanifestinvirtuallyallbodysystems.Prominentfeaturesarenausea,vomiting,colickyabdominalpain,profusewaterydiarrhoea,andexcessivesalivaOtherfeaturesareacutepsychosis,adiffuseskinrash,toxiccardiomyopathy,andseizures.Haematologicalabnormalitiesoccurandrenalfailure,respiratoryfailure,andpulmonaryoedemaarecommon.Neurologicalmanifestationsincludeperipheralneuropathyorencephalopathy.Urinaryarsenicconcentrationisthebestindicatorofrecentpoisoning(12days).Box3:ChronicarsenictoxicityTheclinicalfeaturesmanifestinvirtuallyallbodysystems.Absorbedarsenicaccumulatesintheliver,kidneys,heartandlungs,withsmalleramountsinthemuscles,nervoussystem,gastrointestinaltract,spleen,andlungs.Arsenicisdepositedinthekeratinrichtissues:nails,hair,andskin.Mee’slinesoccurinthefingernailsandtoenails.Themostseriousconsequenceismalignantchangeinalmostallorgansofthebody.Dermatologicalchangesarecommon,suchashyperpigmentationandbothpalmarandsolarkeratoses.Thereisincreasedriskofcardiovasculardisease,peripheralvasculardisease,respiratorydisease,diabetesmellitus,andneutropenia.EffectivetreatmentofchronicarsenictoxicityisnotyetArsenictoxicity County,USA,basedonamatrixforcumulativearsenicexpo-sure,asignicantincreaseinmortalityinbothmalesandfemalesfromhypertensiveheartdiseaseoccurred.InBangla-desh,Rahmanetalin1999reportedanincreasedincidenceofhypertensioninalargestudyof1481subjectsexposedtoarsenicinwellwater.SeventyfourTaiwanesepatientswithischaemicheartdiseasein“arseniasis-hyperendemicvillages”werestudiedandalinkbetweenischaemicheartdiseaseandlongtermarsenicexposurewassuggested.7273Arseniccausesdirectmyocardialinjury,cardiacarrhyth-andcardiomyopathy.Blackfootdiseaseisauniqueper-ipheralvasculardisease,causinggangreneofthefootuniquetoalimitedareaonthesouthwesterncoastofTaiwan,duetolongtermexposuretohigharsenicinartesianwellwater.PeripheralvasculardiseaseisalsoreportedfromChile.NeurologicalsystemTheneurologicalsystemisthemajortargetforthetoxiceffectsofanumberofmetals,especiallytheheavymetalssuchasmercury,lead,andarsenic.Theneurologicaleffectsaremanyandvaried.ThemostfrequentndingisaperipheralneuropathymimickingGuillain-Barrésyndromewithsimilarelectromyographicndings.Theneuropathyisinitiallysensorywithagloveandstockinganaesthesia.Theeffectsoftoxicityalsoincludechangesinbehaviour,confusion,andmemoryloss.Cognitiveimpairmentwasreportedintwoworkersfrom14–18monthsofexposureandmentalfunctionreturnedtonormalafterwithdrawalfromthesourceofarsenic.Anincreasedprevalenceofcerebrovasculardisease,especiallycerebralinfarction,wasobservedinalargestudyof8102menandwomenwhoexperiencedlongtermarsenicexposurefromwellwater.GenitourinarysystemTheMillardCountystudyalsoreportedanincreasedmortalityfromnephritisandprostatecancer.etalin1997analysedcancerregistrydata(1980–87)oftumoursofthebladderandkidneyinTaiwanandreportedthathigharseniclevelsindrinkingwaterfromwellswereassociatedwithtransitionalcellcarcinomasofthebladder,kidney,ureterandallurethralcancersinbothmalesandfemales,andadenocarcinomasofthebladderinmales.Theauthorssuggestthatthecarcinogenicityofarsenicmaybecell-typespecic.Incontrast,astudyfromFinlandfoundanassociationwithbladdercancerriskbutnotkidneycancer,despiteverylowarsenicconcentrationsinthedrilledwells.Moredataarerequiredtoestablisharmcausalrelationshipbetweenarsenicingestionandadverseoutcomesduringpregnancyandonneonatalmorbidityandmortality.InpregnantAndeanwomenwhoconsumedwaterwitharsenicconcentrationsofabout200g/l,arsenicincordblood(9wasalmostashighasinmaternalblood(11g/l).Inthesamegroupplacentalarsenicwas34g/lcomparedwith7g/linwomenunexposedtoarsenic.TheresultsofstudiesbyConchaandcolleaguesintheAndesinArgentinaaddanotherdimensiontothisproblem.Thefetus,andinfantsandchildrenwhoarebreastfed,areexposedtoarsenictoxicityfromthemother.RespiratorysystemStudiesfromWestBengal,Indiadrawattentiontobothrestrictiveandobstructivelungdisease.Respiratorydiseasewasmorecommoninpatientswiththecharacteristicskinlesionsofchronicarsenictoxicity.SimilarndingsofanassociationbetweenskinmanifestationsandlungdiseasewasreportedinChileanchildren.Thepossibilityofincreaseddepositionofarsenicinthelung,althoughthereasonisnotknown,issupportedbynecropsystudiesinalimitednumberofpatients.8687AnincreasedincidenceofbronchitisoccursinastudyonpatientswithblackfootdiseaseinTaiwan.EndocrineandhaematologicalsystemsExposuretohighconcentrationsofarsenicisassociatedwithanincreasedriskofdiabetesmellitus.7388Inchronicarsenictoxicityneutropeniaoccurs.MalignantdiseaseTherelationshipbetweenarsenicandmalignancyisofgrow-ingconcernasmanymillionsofpeoplearepotentialvictims.InBangladeshandIndiaarsenicisassociatedwithskin,lung,liver,kidney,andbladdercancers.Thereisevidencefromothercountriesthatarsenicexposurecausesmalignanciesoftheskin,lung,6990liver,kidney,490andbladder.DatafromTaiwanalsodocumentsmalignanciesofthebladder,kidney,skin,lung,nasalcavity,bone,liver,larynx,colon,andstomachaswellaslymphoma.Themechanisms,thoughnotfullydetermined,arepossiblyanadverseaffectonDNArepair,methylationofDNA,andincreasedfreeradicalformationandactivationoftheproto-oncogenec-myc.Arsenicmayactasaco-carcinogen,tumourpromoter,ortumourprogressorundercertaincircumstances.Highlevelsofarsenicareteratogenicinanimals.StructuralchromosomeaberrationswerestudiedinagroupofindividualswhoconsumedarsenicfromwellwaterinFinlandandtheassociationwasstrongerincurrentusersthaninthe10subjectswhohadstoppedusingthecontaminatedwellwaterfor2–4monthsbeforesampling.Analysesofblood,urine,andhairsamplesareusedtoquantifyandmonitorexposure.Levelsbetween0.1and0.5mg/kgonahairsampleindicatechronicpoisoningwhile1.0to3.0mg/kgindicatesacutepoisoning.ARSENICDEFICIENCYInanimalsdeciencyismanifestasincreasedmortality,reducedfertility,increasedspontaneousabortionrate,lowbirthweightinoffspring,anddamagetoredbloodcells.ECONOMICCOSTSOFCONTAMINATIONTheeconomicsignicanceofarsenictoxicityincludesmedicalexpenses,incomeloss,andreducedcropproductivityandqualityduetosoilandwatercontamination.Thecurrenthealth,economic,andnutritionalproblemswouldbegreatlycompoundedwheninformationregardingarseniccontamina-tionofthefoodchainisbetterknownandifagriculturalproductsandlivestockarefoundtobecontaminated.TheseissuesareofseriousconcernparticularlyinBangladeshwhere97%oftheruralpopulationreliesongroundwaterfordrink-ing,cooking,andirrigation.PREVENTION,MANAGEMENT,ANDFUTUREThehumantragedyduetoarsenictoxicityismostacuteinthedevelopingworldwhereincountriessuchasBangladeshthelivesofmillionsofpeopleareaffected.Insolvingtheincreasingproblemofarseniccontaminationandillhealth,manyissuesneedtobeclaried.InformationisrequiredtodetermineifthereisathresholdforcarcinogeniceffectstomanifestandalsotodenethedoseanddurationofStudiesarerequiredtolinktoxicmanifestationswithpossiblegeneticpolymorphism,age,gender,nutritionalstatus,andtheprotectiveroleofvitamins,minerals,andanti-oxidants.ThereisamarkedvariationinclinicalfeaturesamongindividualsinthesamehouseholdasiscommonlyseeninBangladesh.Thismaybedueto“slow”or“fast”methy-latorsofarsenicsimilartopatientswithinammatoryboweldiseasewhoare“slow”or“fast”acetylatorswhothereforeresponddifferentlytotreatmentwithsalicylate.Theprovisionofsafedrinkingwaterisapriority.Avarietyofmethodsofdiversecomplexityareavailabletoremovearsenicfromdrinkingwater.Themethodology,especiallyin developingcountries,thatisurgentlyrequiredshouldbeaffordable,sustainablebythepopulation,andcosteffective.Amongthemethodsavailableforremovingarsenicfromwaterareprocessesofprecipitationorionexchange.Filtrationofarsenicfromtubewellshasspawnedarangeofltersofvaryingsophisticationandcostandissuesofaffordability,efciency,andmaintenancearelinkedwiththeiruse.Impor-tantly,theprocessandcostofdisposingthearsenicsequesteredafterltrationneedscarefulconsideration.Prom-isingstudiesarereportedusingirontreatednaturalmaterialssuchasirontreatedactivatedcarbon,irontreatedgelbeads,andironoxidecoatedsand,andoftheseironoxidecoatedsandwasthemosteffectivecompound.TheStevenstechnol-ogyforarsenicremovalisinexpensiveandinvolvesmixingasmallpacketofpowdercontainingironsulphateandcalciumhypochloriteinalargebucketofwater,whichisthenlteredthroughseveralcmofsand.Oneattractiveandinexpensiveoptionthatiswidelyavailableistoharvestrainwaterandharnesssurfacewater.InBangladeshthevolumeofwaterthatowsintotheBayofBengalissecondonlytothatowingintotheAmazonbasin.Bangladeshhasanannualrainfallof1500–2000mmwitheasternareasofthecountryreceiving3500mm.TheoptionofharnessingthisnaturalwealthofBangladeshhasreceived,fromavailablepublisheddata,insufcientattention.However,thecheapestsolutionwoulddependoncommunitygoodwillencouragingtheuseofaneighbour’swell(wellsharing)thatisnotcontaminated.Morethan90%ofpeopleinBangladeshlivewithin200mofaclean,safesourceofwellwater.Notreatmentofprovenbenetiscurrentlyavailabletotreatchronicarsenictoxicity.Treatmentoptionsadvocatedarevita-minandmineralsupplementsandantioxidanttherapy.Thebenetsofthesetreatmentmeasuresneedtobeevidencebasedtoreceiveendorsementandwiderapplication.Atacellularlevel,inviewoftheapoptoticmechanismofactionofarsenic,theeffects,especiallyofantioxidantsaretheoreticallyofvalue.Howeverthebenetsofthesecom-poundsatcellularlevelneedvalidationinhumansubjectswithchronicarsenictoxicity.Atpresent,inchronicpoisoning,therapyislimitedtosupportivemeasures.MrEugeneYNgaiandMrChrisSeniorclariedanumberofissuesforwhichIamgrateful.IalsothankMrAustinMiltonandMrsMaryDenysforworkonthemanuscript.TheauthorisAssociateProfessorofMedicineattheUniversityofQUESTIONS(TRUE(T)/FALSE(F);ANSWERSATENDOFREFERENCES)Q1.Themainsourceofarsenicthatcontaminatesdrinkingwaterisfromindustrialsourcessuchasmining.Q2.Inchronicarsenicpoisoningthediagnosticpigmentarychangesoccuronlyinthepalmsandnotthesolesofthefeet.Q3.Thecentralnervoussystemmanifestationsofchronicarsenictoxicityincludecerebralinfarction,changesinbehav-iour,confusion,andmemoryloss.Q4.Inregardtocardiovascularsystemmanifestations,arsenicmaycausedirectmyocardialinjury,cardiacarrhythmias,cardiomyopathy,andinvariablyperipheralvasculardisease.Q5.Arsenicinducesapoptosisbyreleasinganapoptosis-inducingfactorfromthemitochondrialintermembranespace.Q6.Thetreatmentcurrentlyusedinchronicarsenictoxicityconsistsofvitaminandmineralsupplementsandantioxidanttherapythathavedocumentedobjectivebenets.MatschullatJ.Arsenicinthegeosphereareview.TheScienceoftheTotalEnvironmentGebelT.ConfoundingvariablesintheenvironmentaltoxicologyofZawM,EmettMT.Arsenicremovalfromwaterusingadvancedoxidationprocesses.ToxicolLettLewisDR,SouthwickJW,OuelletHellstromR,etal.DrinkingwaterarsenicinUtah:acohortmortalitystudy.EnvironHealthPerspectChowdhuryUK,BiswasBK,ChowdhuryTR,etal.GroundwaterarseniccontaminationinBangladeshandWestBengal,India.EnvironHealthNicksonR,McArthurJ,BurgessW,etal.ArsenicpoisoningofBangladeshgroundwater.BritishGeologicalSurveyandMottMacDonaldLtd(UK)GroundwaterstudiesforarseniccontaminationinBangladesh,phaseI:rapidinvestigationphase.Mainreportsummary,1999:S1MukherjeeAB,BhattacharyaP.ArsenicingroundwaterintheBengalDeltaPlain:slowpoisoninginBangladesh.EnvironRevGuhaMazumderDN,HaqueR,GhoshN,etal.ArseniclevelsindrinkingwaterandtheprevalenceofskinlesionsinWestBengal,India.IntJEpidemiolRegelsonW,KimU,OspinaJ,etal.HemangioendothelialsarcomaofliverfromchronicarsenicintoxicationbyFowler’ssolution.LanderJJ,StanleyRJ,SumnerHW,etal.AngiosarcomaoftheliverassociatedwithFowler’ssolution(potassiumarsenite).NeshiwatLF,FriedlandML,SchorrLesnickB,etal.AmJMedPrystowskySD,ElfenbeinGJ,LambergSI.Nasopharyngealcarcinomaassociatedwithlongtermarsenicingestion.ArchDermatolShenZX,ChenGQ,NiJH,etal.Useofarsenictrioxide(As2O3)inthetreatmentofacutepromyelocyticleukemia(APL):II.Clinicalefficacyandpharmacokineticsinrelapsedpatients.BergstromSK,GillanE,QuinnJJ,etal.Arsenictrioxideinthetreatmentofapatientwithmultiplyrecurrent,ATRAresistantpromyelocyticleukemia:acasereport.JPediatrHematolOncolSoignetSL,MaslakP,WangZG,etal.Completeremissionaftertreatmentofacutepromyelocyticleukemiawitharsenictrioxide.NEnglJFenauxP.ChomienneC.DegosL.TreatmentofacutepromyelocyticClinHaematolZhuJ,ChenZ,LallemandBreitenbachV,etal.Howacutepromyelocyticleukaemiarevivedarsenic.NatRevCancerLorenzoHK,SusinSA,PenningerJ,etal.Apoptosisinducingfactor(AIF):aphylogeneticallyold,caspaseindependenteffectorofcelldeath.CellDeathDifferSusinSA,LorenzoHK,ZamzamiN,etal.Molecularcharacterizationofmit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