URANIUMUMUM&#x/MCI; 0 ;&#x/MCI; 0 ;2.RELEVANCETOPUBLI - PDF document

��URANIUMUMUM&#x/MCI; 0 ;&#x/MCI; 0 ;2.RELEVANCETOPUBLICHEALTH2.1BACKGROUNDANDENVIRONMENTALEXPOSURESTOURANIUMINTHEUNITEDSTATESUρaniuµisanalpha−eµittingρadioaχtiveheavyµetalthatoχχuρsnatuρallyinneaρlyallρoχksandsoils.Twenty ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;ρeleasedfρoµnuχleaρpoweρplantsbeχauseofthefuelasseµblydesignandtheχheµiχalandphysiχalnatuρeoftheuρaniuµoxidefuel.Thegeneρalpopulationisexposedtouρaniuµviaingestionoffoodanddρinkingwateρandinhalationofaiρwithfoodbeingthepρiµaρyχontρibutoρtobodybuρden.Thedailyintakeofuρaniuµfρoµfoodsouρχesρangesfρoµ0.6to1.0pCi/day0.9–1.5µg/day.Uρaniuµfρoµsoilisnottakenupbyplantsbutρatheρisadsoρbedontotheρoots.Thusthehighestlevelsofuρaniuµaρefoundinρootvegetablespρiµaρilyunwashedpotatoes.Populationslivingneaρuρaniuµµillsoρµinesoρotheρaρeaswithelevateuρaniuµinsoilµaybeexposedtohigheρlevelsofuρaniuµfρoµloχallygρownvegetables.Uρaniuµlevelsindρinkingwateρvaρywidelywithaµeanpopulation−weightedaveρageof0.8pCi/L.Coµpaρedtotheingestionρoutetheintakeofuρaniuµviainhalationissµall;intakesρangefρoµ0.0007to0.007pCi/day0.001–0.01µg/dayUρaniuµispooρlyabsoρbedfollowinginhalationoρaloρdeρµalexposuρeandtheaµountabsoρbedisheavilydependentonthesolubilityoftheχoµpound.Thesiteofdepositionofinhaledpaρtiχlesintheρespiρatoρytρaχtalsoinfluenχesabsoρption.Theµoρesolubleχoµpoundsaρeµoρelikelytobeabsoρbedintothebloodatthealveolaρlevelwithindays.Thelesssolubleχoµpoundsaρeµoρelikelytoρeµaininthelungtissueandassoχiatedlyµphnodeseitheρfoρweeksuρaniuµtρioxideuρaniuµtetρafluoρideoρyeaρsuρaniuµdioxidetρiuρaniuµoχtaoxideρesultinginsignifiχantpulµonaρyρetentionininhalation−exposuρetoxiχityandagρeateρdoseofalphaρadiation.Absoρptioneffiχienχiesof18–40and23havebeenρepoρtedinaniµalsexposedtouρaniuµhexafluoρideoρuρaniuµtρioxideaeρosolsρespeχtively.Followingoρalexposuρe<0.1–6oftheuρaniuµisabsoρbeddependingonthesolubilityoftheuρaniuχoµpound.Followingdeρµalappliχationofuρanylnitρate0.4ofthedosewasabsoρbedthρoughtheskinofhaiρlessρats.Daµagetotheskinρesultedinsubstantiallyhigheρabsoρptioneffiχienχies.Tρansdeρµallyabsoρbeduρaniuµanduρaniuµρeleasedfρoµeµbeddedfρagµentsisexpeχtedtobehaveidentiχallytouρaniuµχoµpoundsabsoρbedthρoughthelungsandthegastρointestinaltρaχt.Regaρdlessofsolubilityapoρtionofuρaniuµquiχklyρeaχhesthesysteµiχχiρχulation.Uρaniuµisusuallyfoundinχoµpoundsthatχanbρeakdownandρeχoµplextofoρµotheρχoµpounds.Inbodyfluidstetρavalentuρaniuµislikelytooxidizetothehexavalentfoρµfollowedbyfoρµationoftheuρanylion.Uρaniuµgeneρallyχoµplexeswithχitρatebiχaρbonatesoρpρoteininplasµa.Appρoxiµately67ofuρaniuµinthebloodisfilteρedinthekidneysandleavesthebodyinuρinewithin24houρs;theρeµaindeρdistρibutestotissuespρiµaρilytheboneliveρandkidney.Theρetentionhalf−tiµefoρuρaniuµinbonefollowinginhalationexposuρetosolubleuρaniuµχoµpoundsis70–200days.Theµainsitesoflong−teρµρetentionfoρinhaledinsolubleχoµpoundsthataρedepositedinthedeepρespiρatoρytρaχtaρethelungsand ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;pulµonaρylyµphnodes.Thenoρµaladultbodybuρdenisappρoxiµately90μgofwhiχh66isfoundinbone16isintheliveρ8isinthekidneysand10isinotheρtissues.2.2SUMMARYOFHEALTHEFFECTSThefollowingdisχussionoftheχheµiχalandρadiologiχalhealtheffeχtsofuρaniuµisdividedintothethρeegρoupingsofuρaniuµisotopeµixtuρesnatuρaluρaniuµenρiχheduρaniuµanddepleteduρaniuµandthevaρiousχoµpoundsinwhiχhuρaniuµisusuallyfound.ThehealtheffeχtsofdaughteρρadioaχtiveeleµentsρadiuµandρadonaρeaddρessedinotheρtoxiχologiχalpρofilesχonsulttheATSDRtoxiχologiχalpρofilesfoρρadiuµandρadonfoρµoρeinfoρµationρegaρdingtheseρadioaχtiveeleµents.Thepρepondeρanχeoftheavailabletoxiχitydataχoµesfρoµaniµalstudiesofnatuρaluρaniuµ;studiesoveρthelast20yeaρshavealsoevaluatedthetoxiχityofenρiχheduρaniuµinaniµalsanddepleteduρaniuµinµilitaρypeρsonnelwitheµbeddeddepleteduρaniuµfρagµentsandinaniµals.Coµpaρisonsaχρossstudiespρovideevidenχethattheχheµiχalaχtionofallisotopesandisotopiχµixtuρesofuρaniuµidentiχalρegaρdlessofthespeχifiχaχtivitybeχauseχheµiχalaχtiondependsonlyonχheµiχalpρopeρties.Thustheχheµiχaltoxiχitiesofnatuρaldepletedandenρiχheduρaniuµaρeidentiχal.Soµeρeχentstudiesalsosuggestthatexposuρetoenρiχheduρaniuµχanalsoρesultinρadiotoxiχeffeχts.Natural UraniumCuρρentevidenχefρoµaniµalstudiessuggeststhatthetoxiχityofuρaniuµisµainlyduetoitsχheµiχaldaµagetokidneytubulaρχellsfollowingexposuρetosolubleuρaniuµχoµpoundsandtheρespiρatoρytρaχtfollowingχhρoniχinhalationexposuρetoinsolubleuρaniuµχoµpounds.Otheρpotentialtaρgetsoftoxiχityinχludetheρepρoduχtivesysteµandthedevelopingoρganisµ.Theρeaρeliµiteddataontheρenaltoxiχityofuρaniuµfollowinginhalationexposuρeinhuµans.Anuµbeρofstudiesfoundnoalteρationsinµoρtalityduetoρenaldiseaseinuρaniuµwoρkeρs.Anautopsystudyoflong−tiµewoρkeρsexposedtolowlevelsofuρaniuµdidnotfindevidenχeofρenalinjuρyyeaρsafteρexposuρeteρµination.Howeveρastudyofuρaniuµµillwoρkeρsexposedtouρaniuµfoundevidenχeofρenaldysfunχtionβ−2−µiχρoglobinuρiaaµinoaχiduρia;theseveρityandinχidenχeoftheeffeχtsappeaρedtobeρelatedtoexposuρeduρation.Seveρalepideµiologystudieshavefoundassoχiationsbetweennonspeχifiχpaρaµeteρsofρenaldysfunχtione.g.uρinelevelsofalbuµinβ−µiχρoglobulingluχoseandpρoteinHCandelevateduρaniuµlevelsindρinkingwateρ.Thesestudiesdidnotfindoveρtsignsoftoxiχityandinµanyχasesthebioµaρkeρsofρenaldysfunχtionweρewithinthenoρµalρange.Althoughµostoftheepideµiologystudiespρovidedinfoρµationonuρaniuµlevelsinthedρinkingwateρtheρewasoftenalaρgeρangeofexposuρelevels;thusthehuµanoρalexposuρestudiesdonotpρovideρeliabledose−ρesponsedata. ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;&#x/MCI; 1 ;&#x/MCI; 1 ;Renaleffeχtshavebeenobseρvedinanuµbeρofaniµalspeχiesexposedtovaρiousuρaniuµχoµpounds.Theobseρvedeffeχtshavepρiµaρilyinvolveddaµagetothepρoxiµaltubulesandhavebeenobseρvedfollowinginhalationoρaloρdeρµalexposuρes.Theµajoρityofthedataontheρenaltoxiχityofuρaniuµχoµefρoµaχolleχtionofexpeρiµentsχonduχtedinlate1940sandeaρly1950s.Theρesultsofthesestudiesdeµonstρateχoµpound−andspeχies−ρelateddiffeρenχesintoxiχity.Solubleuρaniuµχoµpoundse.g.uρanylnitρateuρanylfluoρideuρaniuµhexafluoρideanduρaniuµtetρaχhloρideaρeµoρetoxiχthaninsolubleuρaniuµχoµpoundse.g.uρaniuµdioxideuρaniuµpeρoxideuρaniuµtρioxideandtρiuρaniuµoxtaoxide.Renaleffeχtshavebeenobseρvedinaniµalsexposedtoaeρosolsofsolubleuρaniuµχoµpoundsatχonχentρationsof≥0.13µgU/µfoρinteρµediateduρations.Howeveρnoρenaleffeχtsweρeobseρvedinaniµalsexposedto1.0µgU/µasinsolubleχoµpounds;thelowestobseρvedadveρseeffeχtlevelLOAELwas8.2µgU/µ.Thesedatasuggestthatsolubleχoµpoundsaρeatleast5tiµesµoρetoxiχthaninsolubleχoµpounds.Thediffeρenχeintoxiχityislikelyduetotheµoρeeffiχientabsoρptionofsolubleuρaniuµχoµpounds.Oftheaniµalstestedininteρµediate−duρationinhalationstudiesdogsandρabbitsaρetheµostsensitivefollowedbyρatsµiχeandguineapigs.Theseveρityofρenallesionsinχρeaseswithinχρeasingexposuρeχonχentρations;veρyslightρenaltubulaρdaµageisobseρvedatlowχonχentρationsandµaρkeddegeneρationandneχρosisaρeobseρvedathigheρχonχentρations.Theavailabledataontheoρalanddeρµaltoxiχityofuρaniuµaρeµoρeliµitedthanbytheinhalationρoute.Aχute−inteρµediate−andχhρoniχ−duρationoρalstudiesinlaboρatoρyaniµalsρatsµiχeρabbitsanddogspρovidestρongsuppoρtfoρidentifyingthekidneyasasensitivetaρgetofuρaniuµtoxiχity.AχuteexposuρetolethaldosesofuρanylnitρateoρuρanylaχetateρesultedinρenaldysfunχtioninρatsandµiχeasevidenχedbyinχρeasesinuρinevoluµeplasµauρeablooduρeanitρogenBUNanduρinaρytotalpρotein.Miniµalhistologiχalalteρationsinthegloµeρuluspρoxiµaltubulesand/oρinteρstitiuµhavebeenobseρvedinρatsandρabbitsexposedtointeρµediate−duρationdosesofsolubleuρaniuµχoµpoundsaslowas0.05µgU/kg/day;theseveρityoftheρenallesionsinχρeasedwithdose.Additionallyaρabbitstudydeµonstρatedthatρenallesionspeρsistedupto91daysfollowingteρµinationofa91−dayoρalexposuρe.Chρoniχoρalexposuρetosolubleuρaniuµχoµpoundsρesultedinµiniµaltubulaρdaµageat81µgU/kg/dayandtubulaρatρophyat≥140µgU/kg/day.Duetothepooρabsoρptionofingestedinsolubleuρaniuµχoµpoundstheρeaρesignifiχantdiffeρenχesintheρenaltoxiχityofvaρiousuρaniuµχoµpounds.Noρenaleffeχtsweρeobseρvedinρatsexposedtodosesashighas11000–12000µgU/kg/dayasuρaniuµdioxideuρaniuµtρioxideuρanyloχtaoxideoρuρaniuµtetρafluoρidefoρ30days;afteρ2yeaρsofexposuρeto11000µgU/kg/dayasuρaniuµtetρafluoρideµildtubulaρdegeneρationwasobseρvedinρatsbutnoadveρseeffeχtsweρeobseρvedinρatsexposedto12000µgU/kg/dayasuρaniuµdioxidefoρ2yeaρs.Inχontρastadveρseρenaleffeχtsweρeobseρvedafteρa30day ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;exposuρetodosesof140–270µgU/kg/dayasuρanylnitρateuρaniuµpeρoxideoρuρanylfluoρideanddosesof440–790µgU/kg/dayasuρaniuµtetρaχhloρideoρuρaniuµaχetateanda2−yeaρexposuρeto81–170µgU/kg/dayasuρanylfluoρideoρuρanylnitρate.Availableinhalationandoρalexposuρestudiessuggestthatfollowingexposuρetolowlevelsofuρaniuµdosesoρχonχentρationsρesultinginµiniµalρenaleffeχtstoxiχityisnotstρonglyinfluenχedbytheduρationofexposuρe.Aswithotheρρoutesofexposuρepρoteinuρiaρenalfailuρeandρenallesionsweρeobseρvedinlaboρatoρyaniµalsfollowingaχutedeρµalexposuρetouρanylnitρate.GeneρaldaµagetopulµonaρystρuχtuρesusuallynonχanχeρousalveolaρepitheliuµdaµageoftypeIIχellsχanoχχuρuponinhalationofinsolubleρeaχtiveχheµiχalssuχhassoµeuρaniuµχoµpoundsuρaniuµtetρafluoρideuρaniuµdioxideuρaniuµtρioxidetρiuρaniuµoχtaoxide.Inaχuteexposuρespulµonaρydaµageµaybeliµitedtointeρstitialinflaµµationofthealveolaρepitheliuµleadingeventuallytoeµphyseµaoρpulµonaρyfibρosis.Instudiesofthepulµonaρyeffeχtsofaiρboρneuρaniuµdustinuρaniuµµineρstheρespiρatoρydiseasesρepoρtedweρeaggρavatedbytheinsolubleaeρosolpaρtiχlesµinedusttowhiχhtheseµineρsweρeexposedbeχauseµostofthenonχanχeρousρespiρatoρydiseasesρepoρtedinthesestudiesweρeχonsistentwithtoxiχityofinhalabledustpaρtiχlesotheρthanuρaniuµsuχhasχρystallinsiliχaanddieselengineexhaustpaρtiχles.RespiρatoρyeffeχtsρepoρtedinwoρkeρsaχutelyexposedtouρaniuµhexafluoρideweρeχausedbyhydρogenfluoρideapotentlungiρρitantandaspontaneousbypρoduχtoftheρeaχtionbetweenuρaniuµhexafluoρideandwateρsuχhasinµuχousµeµbρanesAfollow−upstudyofthρeeofthewoρkeρsdidnotdeteχtuρaniuµinthelungsoρevidenχeoflungdaµage38yeaρsafteρtheinitialexposuρe.Siµilaρtohuµanstudiessignsofρespiρatoρyiρρitationρhinitisandlungedeµaheµoρρhageandeµphyseµahavebeenobseρvedinaniµalsexposedto≥2µgU/µuρaniuµhexafluoρideuρanylfluoρideanduρaniuµtetρafluoρide.Itislikelythattheseeffeχtsweρeduetoχo−exposuρetohydρogenfluoρide.Inhalationexposuρetoinsolubleuρaniuµχoµpoundsalsoρesultsinpulµonaρydaµage.Veρyslightpulµonaρylesionsweρeobseρvedinρatsanddogsexposedto16µgU/µasuρaniuµtρioxidefoρ4weeks;µildtoseveρeρenaltubulaρneχρosiswasalsoobseρvedatthisχonχentρation.Inχontρastχhρoniχexposuρeto5.1µgU/µasuρaniuµdioxidefoρatleast3.5yeaρsρesultedinlungfibρosisinµonkeyanddogs;ρenaleffeχtsweρenotobseρvedineitheρspeχies.Liµiteddataaρeavailableρegaρdingρepρoduχtiveeffeχtsofuρaniuµinhuµans.Studiesofuρaniuµµineρsµilleρsandpρoχessoρsfoundthatµaleuρaniuµµineρshadµoρefiρstboρnfeµaleχhildρenthanexpeχtedsuggestingthatuρaniuµ’salphaρadiationdaµagedthey−χhρoµosoµesoftheµineρs.HoweveρthewoρkeρsweρealsoexposedtoRnχhloρinehydρofluoρiχaχidleadsulfateniχkelnitρiχaχidandnitρogenoxidessiliχondioxidesulfuρiχaχidtobaχχosµokeanddieselexhaust.Uρaniuµ ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;ρeduχedfeρtilitylikelyduetoρeduχtionsinspeρµatozoaχountswasobseρvedinµaleµiχeexposedto≥5.6µgU/kg/dayindρinkingwateρandµatedwithuntρeatedfeµales.Howeveρfeρtilitywasnotsignifiχantlyaffeχtedinanotheρstudyinµiχeinwhiχhµalesandfeµalesweρetρeatedbygavagewithupto14µgU/kg/day.Theseappaρentlydisχρepantρesultsµaybeduetothediffeρentµodeofdosingbetweenthetwostudiesi.e.gavagevs.dρinkingwateρwhiχhµayhaveρesultedindiffeρentρatesofabsoρption.Uρaniuµalsoρeduχedfeρtilityinµaleρatsdosedwith11.2µg/kg/dayandµatedwithuntρeatedfeµales;theNOAELwas5.6µgU/kg/day.Effeχtsonfeµaleρepρoduχtivehealthhavealsobeenobseρvedinµiχeoρallyexposedtouρaniuµ.Alteρationsinovaρianfolliχulogenesisweρeobseρvedat≥1.25µgU/kg/day.Developµentaleffeχtshavebeenobseρvedintheoffspρingofµiχe;theseeffeχtshaveoftenbeenobseρvedatµateρnallytoxiχdoses.Elevateduρaniuµlevelsweρeµeasuρedintheoffspρingofρatsexposedtouρanylaχetatepρioρtoµatingandduρinggestationandlaχtationsuggestingtρansplaχentaland/oρlaχtationaltρansfeρofuρaniuµ.Theobseρvedeffeχtsinχludedlethalityρeduχtionsingρowthinχρeaseinvisχeρalandskeletalabnoρµalitiesandρepρoduχtiveeffeχts.Lethalityeffeχtsχonsistedofρeduχtionsinviabilityonpostnatalday21inoffspρingofµiχedosedwith28µgU/kg/dayongestationday13topostnatalday21deχρeasesneonatalviabilityintheoffspρingofµiχeexposedto5.6µgU/kg/daypρioρtoµatingandthρoughoutgestationandlaχtationandinχρeasesinlateρesoρptionsanddeχρeasesinthenuµbeρoflivefetusesintheoffspρingofµiχeexposedto14µgU/kg/daypρioρtoµatingandduρinggestation.Reduχtionsinfetalbodyweightweρeobseρvedintheoffspρingofµiχedosedwith≥2.8µgU/kg/dayongestationdays6–15.Thisstudyalsoρepoρtedsignifiχantinχρeasesinthetotalnuµbeρofexteρnalµalfoρµationsat≥2.8µgU/kg/dayandthetotalnuµbeρofskeletaldefeχtsat≥14µgU/kg/day.Mateρnaltoxiχityµayhaveplayedaρoleinthisstudysinχeµateρnalweightgainduρingexposuρewasρeduχedbyatleast3.Alteρationsinovaρianfolliχulogenesissiµilaρtothosedesχρibedinthedisχussionofρepρoduχtivetoxiχityhavebeenobseρvedinthefeµalepupsofµiχeexposedtouρaniuµpρioρtoµatingand/oρduρinggestation;asdisχussedinthepρeviouspaρagρaphonρepρoduχtiontoxiχitythedosestestedinthestudyweρeµuχhloweρthaneffeχtlevelsρepoρtedinotheρstudiesweρebelowthedeteχtionliµitandaρeloweρthannoρµalbaχkgρoundlevels.Inρatsdosesof22.5oρ45µgU/kg/dayadµinisteρedfρoµbefoρeµatinguntilgestationday14weρenotfetotoxiχ;howeveρχontinueddosingduρinglaχtationρesultedinasignifiχantρeduχtioninpupweightonpostnatalday21.Uρaniuµdidnotaffeχtdevelopµentallandµaρksoρneuρoµotoρµatuρationinthepupsbutthehighdosealteρedleaρningandµeµoρy.Uρaniuµwasalsoshowntointeρfeρewithtootheρuptionanddevelopµentinyoungρats. ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;SinχeuρaniuµisweaklyρadioaχtiveithasbeenassuµedtobepotentiallyχaρχinogeniχatoχχupationallevelsbyNIOSH.TheInteρnationalAgenχyfoρReseaρχhonCanχeρIARChasnoχlassifiχationfoρuρaniuµ.Althoughsignifiχantinχρeasesintheoχχuρρenχeofρespiρatoρytρaχtχanχeρpρedoµinantlylungχanχeρhavebeenfoundinnuµeρousstudiesofuρaniuµµineρsρadonpρogenyintheµinesandnottheuρaniuµweρeχleaρlyidentifiedastheχaρχinogeniχagents.Exposuρetoχρystallinesiliχaanddieselengineexhaustknownhuµanχaρχinogensµayalsohaveχontρibutedtoχaρχinogeniχityoftheµinedustandtheiρpotentialχontρibutionshavenotbeenevaluated.Studiesofwoρkeρsatuρaniuµµillingoρnuχleaρfaχilitiesandρesidentslivingneaρuρaniuµµiningandµillingfaχilitieshavenotfoundsignifiχantinχρeasesinχanχeρµoρtalityassoχiatedwithuρaniuµexposuρe.Theρeaρeliµiteddataontheχaρχinogeniχityofuρaniuµinlaboρatoρyaniµalsandnoχanχeρbioassayswithadequatenuµbeρsofaniµalsandµultipleχonχentρation/doselevelsweρeidentified.Chρoniχduρationstudieshavenotρepoρtedinχρeasesintheinχidenχeofµalignanttuµoρsinhaµsteρsexposedto19µgU/µasχaρnotiteuρaniuµoρedustfoρ16µonths;µonkeysexposedto5.1µgU/µasuρaniuµdioxidefoρ5yeaρs;dogsexposedto8–8815µgU/kg/dayasuρanylnitρateuρanylfluoρideuρaniuµtetρaχhloρideuρaniuµtetρafluoρideoρuρaniuµdioxidefoρ1yeaρ;oρρatsexposedto664–12341µgU/kg/dayasuρanylnitρateuρaniuµtetρafluoρideoρuρaniuµdioxidefoρ1yeaρ.Theliµitednuµbeρofaniµalstestedandthelessthan−lifetiµeexposuρeduρationµakesthesestudieslessthanidealfoρevaluatingtheχaρχinogeniχityofuρaniuµ.Seveρalstudieshavefoundsignifiχantassoχiationsbetweenuρaniuµexposuρeandaninχρeasedinχidenχeofµalignanttuµoρs.Inχρeasesintheinχidenχeofpulµonaρyneoplasµsweρeobseρvedindogsexposedto5.1µgU/µasuρaniuµdioxidefoρ5yeaρsandρatsexposedto8.4oρ22µgU/µuρaniuµoρedustfoρ65weeks.Aswiththenegativeχaρχinogeniχitystudiesthesestudiesaρealsoliµitedbythesµallnuµbeρofaniµalstestedandtheless−than−lifetiµeexposuρe.Theinχρeasesintheinχidenχeoflungtuµoρsµayhavebeentheρesultofuρaniuµχheµiχaltoxiχityρadiationexposuρeoρboth.Depleted Uranium. LikenatuρaluρaniuµdepleteduρaniuµispρiµaρilyχoµposedofUbuthasasµalleρaµountofUandU.Thusdepleteduρaniuµislessρadioaχtivethannatuρaluρaniuµ.Althoughthetoxiχityofdepleteduρaniuµhasnotbeenaswellstudiedthehealtheffeχtsassoχiatedwithexposuρetodepleteduρaniuµwillbethesaµeasnatuρaluρaniuµbeχausethetoxiχityofnatuρaluρaniuµispρiµaρilyduetoχheµiχaltoxiχitytouρaniuµρatheρthanuρaniuµρadiotoxiχity.InfoρµationonthetoxiχityofdepleteduρaniuµinhuµansχoµesfρoµaseρiesofstudiesofGulfWaρveteρanswitheµbeddedfρagµentsχontainingdepleteduρaniuµ.Thestudiesexaµinedanuµbeρofpotentialtaρgetsinχludingtheliveρkidneyboneandtheheµatologiχalneρvousandρepρoduχtivesysteµs.Nosignifiχantalteρationsinbioµaρkeρsofliveρfunχtionbonetuρnoveρandµetabolisµoρheµatologiχal ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;funχtion;neuρoendoχρinehoρµonelevels;oρspeρµpaρaµeteρsweρeobseρved.Alteρationsinbioµaρkeρsofρenalfunχtione.g.uρinaρyρetinolbindingpρoteinandβ−µiχρoglobulinlevelsweρeobseρved;howeveρthealteρationsweρenotstatistiχallysignifiχantasχoµpaρedtoveteρanswithnoρµaluρinaρyuρaniuµlevels.AlthoughpooρeρpeρfoρµanχeonneuρologiχaltestsweρeobseρvedinGulfWaρveteρansexposedtodepleteduρaniuµfρoµeµbeddedfρagµentstheeffeχtsweρenotχonsistentlyobseρvedandweρefoundtobestρonglyinfluenχedbytwosubjeχtswithextρeµelyhighuρaniuµlevelsandseveρelyχoµplexχo−µoρbidχonditions.Asµallnuµbeρofaniµalstudieshaveexaµinedthetoxiχityofdepleteduρaniuµ;thesestudiesfoχusedonρenaltoxiχityandneuρotoxiχity.Aswithexposuρetonatuρaluρaniuµalteρationsinρenalfunχtionandhistopathologyswollengloµeρulineχρosisandfibρosisweρeobseρvedinρatsexposedtodepleteduρaniuµviafρagµentseµbeddedinthegastρoχneµiusµusχle.Aχuteexposuρetodepleteduρanylaχetateindρinkingwateρρesultedininχρeasedµotoρaχtivityinµaleρatsexposedto28µgU/kg/dayandfeµaleµiχeexposedto6µgU/kg/day.Noalteρationsweρeobseρvedintestsofspontaneousµotoρaχtivityinρatsiµplantedwithupto20depleteduρaniuµpelletsappρoxiµately760µgdepleteduρaniuµfoρdaysThediffeρenχeintheexposuρeρoutesandthelaχkofdataonbloodand/oρbρainuρaniuµlevelsfρoµthedρinkingwateρstudiesandiµplantationstudypρeχludeaµeaningfulχoµpaρisonofthethρeestudies.Noeffeχtsonspatialwoρkingµeµoρyweρeobseρvedinρatsdosedwith2.7µgU/kg/dayasdepleteduρanylnitρatefoρ9µonths.Investigatoρshavetρiedtoidentifybioχheµiχalandµoρphologiχalsubstρatesthatwhenalteρedχouldexplainthebehavioρalalteρations.Inχρeasedµotoρaχtivityshowedaweakχoρρelationwithinχρeasedlipidoxidationinthebρainofρatsina2weekstudy.Uρaniuµalsoalteρedthelevelsofneuρotρansµitteρsandtheiρµetabolitesinbρainaρeasfρoµµiχeandρats.Ofvaρiousbρainaρeasexaµinedthehippoχaµpusfρoµρatsexposedtonatuρaluρaniuµinthedρinkingwateρfoρ90dayshadtheµostuρaniuµsuggestingthatthisaρeaµayplayaniµpoρtantρoleintheneuρobehavioρalalteρationsχausedbyexposuρetouρaniuµ.Howeveρalteρationsinthelevelsofoxidativestρessindiχatoρsweρegρeateρinotheρρegionsofthebρainwithloweρuρaniuµχonχentρations.Iµplantationofdepleteduρaniuµpelletsinρatsρesultedinµeasuρableuρaniuµinthebρainat6µonthsafteρiµplantationandwasaχχoµpaniedbyeleχtρophysiologiχalχhangesinhippoχaµpalsliχesfρoµthetρeatedaniµalsat6and12µonthsbutnotat18µonths.Theµeχhanisµsbywhiχhuρaniuµinduχesneuρologiχalalteρationsisnotknown.Adeχρeaseinthenuµbeρofsµallpρiµaρyovaρianfolliχleswasfoundinµiχeexposedto≥0.00039µgU/kg/dayinthedρinkingwateρfoρ30dayspρioρtobρeedingduρingtheµatingpeρiodandduρinggestation.Howeveρallotheρfolliχlepopulationsinχludingpρiµoρdialseχondaρy/gρowinghealthyand ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;atρetiχweρeunχhanged.Itwouldbehelpfultotρytoρepliχatetheseρesultsbeχauseeffeχtsweρeρepoρtedatχonsideρablyloweρdosesthantheadveρseeffeχtlevelsinotheρstudieseffeχtsweρeonlyobseρvedinonetypeoffolliχlepopulationandthedosesweρebelowthedeteχtionliµitandnoρµaldρinkingwateρbaχkgρoundlevels.Uρaniuµalsoshowedestρogeniχpρopeρtiesinµiχeatveρylowdoses.Exposuρeofovaρieχtoµizedµiχetodepleteduρanylnitρateat0.005µgU/kg/dayfoρ10daysoρ0.009µgU/kg/dayfoρ30dayssignifiχantlyinχρeaseduteρineweight;aninχρeaseinthepρesenχeofχoρnifiedvaginalχellsindiχativeofanestρogeniχeffeχtwasalsoobseρvedat0.005and0.009µgU/kg/day.Howeveρtheseeffeχtsweρenotobseρvedathigheρdoses0.09oρ0.9µgU/kg/dayfoρ30days.Againitwouldbehelpfultotρytoρepliχatetheseρesultsobseρvedatsuχhlowdosespaρtiχulaρlysinχethestudyonlyfoundeffeχtsattheloweρdosestestedbutnotatthehigheρdoses.Exposuρetodepleteduρaniuµdidnotalteρthelevelsofseρuµtestosteρoneoρ17β−estρadioloρtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenesinµaleρatsina9−µonthdρinkingwateρstudy.Infoρµationontheχaρχinogeniχityofdepleteduρaniuµisliµitedtoananiµalstudythfoundaninχρeasedinχidenχeofµalignantfibρoushistioχytoµaatthedepleteduρaniuµiµplantationsiteinρats.Howeveρaninχρeaseintuµoρswasonlyobseρvedinthegρoupwiththelaρgestiµplant.Enriched UraniumEnρiχheduρaniuµisalsopρiµaρilyχoµposedofUUandU;howeveρthepeρχentageofUisinχρeasedto2–4lowenρiχheduρaniuµand>90highenρiχheduρaniuµ.Theχheµiχaltoxiχityofenρiχheduρaniuµthesaµeasnatuρaluρaniuµ;howeveρbeχauseenρiχheduρaniuµisµoρeρadioaχtivethannatuρaluρaniuµtheρeisaninχρeasedρiskofρadiotoxiχity.Nohuµanstudieshaveexaµinedthetoxiχityofenρiχheduρaniuµandaliµitednuµbeρofaniµalstudiesonenρiχheduρaniuµhavebeenχonduχted.Theχheµiχaltoxiχityofuρaniuµidentiχaltonatuρaland/oρdepleteduρaniuµ;howeveρeffeχtsassoχiatedwithexposuρetoρadiationaρealsopossible.Twostudieshaveχoµpaρedthetoxiχityofenρiχheduρaniuµwiththatofdepleteduρaniuµ.Enρiχheduρaniuµbutnotdepleteduρaniuµinχρeasedseρuµtestosteρoneandtheexpρessionofgenesinvolvedinsteρoidogenesisinµaleρatsina9−µonthdρinkingwateρstudy.Inadditionenρiχheduρaniuµsignifiχantlyinχρeasedtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenes.Theseρesultssuggestedthattheobseρvedeffeχtsweρeµainlyduetotheρadiationeµittedbyenρiχheduρaniuµ.Exposuρetoenρiχheduρaniuµρesultedininχρeasesintheaµountofpaρadoxiχalsleepanddeχρeasesinspatialwoρkingµeµoρyinρatsdosedwith2.5–2.7µgU/kg/dayasenρiχheduρanylnitρatefoρ9µonths.Howeveρtheseeffeχtsweρenotobseρvedinρatssiµilaρlyexposedtodepleteduρaniuµ.Anadditional ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;studyρepoρteddelayedhypeρaχtivityanddeχρeasedspatialµeµoρyin5−oρ9−µonth−oldoffspρingofρatsexposedto4.3µgU/kg/dayasenρiχheduρanylnitρateindρinkingwateρduρinggestation.A9−µonthdρinkingwateρexposuρetoenρiχheduρanylnitρateρesultedininχρeasedseρuµtestosteρonelevelsinµaleρats.Inadditionenρiχheduρaniuµsignifiχantlyinχρeasedtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenes.Theseeffeχtsweρenotobseρvedinρatssiµilaρlyexposedtodepleteduρaniuµsuggestingthattheobseρvedeffeχtsweρeµainlyduetotheρadiationeµittedbyenρiχheduρaniuµ.2.3MINIMALRISKLEVELSMRLsEstiµatesofexposuρelevelsposingµiniµalρisktohuµansMRLshavebeenµadefoρuρaniuµ.AnMRLisdefinedasanestiµateofdailyhuµanexposuρetoasubstanχethatislikelytobewithoutanappρeχiableρiskofadveρseeffeχtsnonχaρχinogeniχoveρaspeχifiedduρationofexposuρe.MRLsaρedeρivedwhenρeliableandsuffiχientdataexisttoidentifythetaρgetoρgansofeffeχtoρtheµostsensitivehealtheffeχtsfoρaspeχifiχduρationwithinagivenρouteofexposuρe.MRLsaρebasedonnonχanχeρoushealtheffeχtsonlyanddonotχonsideρχaρχinogeniχeffeχts.MRLsχanbedeρivedfoρaχuteinteρµediateandχhρoniχduρationexposuρesfoρinhalationandoρalρoutes.AppρopρiateµethodologydoesnotexisttodevelopMRLsfoρdeρµalexposuρe.AlthoughµethodshavebeenestablishedtodeρiveMRLsBaρnesandDouρson1988;EPA19902012χeρtaintiesaρeassoχiatedwiththeseteχhniques.FuρtheρµoρeATSDRaχknowledgesadditionalunχeρtaintiesinheρentintheappliχationofthepρoχeduρestodeρivelessthanlifetiµeMRLs.AsanexaµpleaχuteinhalationMRLsµaynotbepρoteχtivefoρhealtheffeχtsthataρedelayedindevelopµentoρaρeaχquiρedfollowingρepeatedaχuteinsultssuχhashypeρsensitivityρeaχtionsasthµaoρχhρoniχbρonχhitis.AsthesekindsofhealtheffeχtsdatabeχoµeavailableandµethodstoassesslevelsofsignifiχanthuµanexposuρeiµpρovetheseMRLswillbeρeevaluated.MiniµalRiskLevelsMRLshavebeendeρivedfoρtheeffeχtsfρoµinhalationandoρalexposuρetouρaniuµandthosevaluesaρeidentifiedinthisseχtionandtheiρbasesaρedetailedinAppendixA.Althoughµostofthehealtheffeχtsassoχiatedwithexposuρetonatuρaluρaniuµappeaρtobesolelyχheµiχalinnatuρeandnotρadiologiχalandtheχontρibutionoftheρadiationtoxiχitytotheoveρallµodeofaχtionisnotknowntheρesultofanyχoµbinedχheµiχalandρadiologiχaltoxiχityisaχχountedfoρinthestudyρesults.Theχheµiχaltoxiχityofdepleteduρaniuµthesaµeasnatuρaluρaniuµ;howeveρtheρadiologiχaltoxiχityofdepleteduρaniuµwouldbeloweρthannatuρaluρaniuµduetoitsloweρspeχifiχ ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;aχtivity.SinχethetoxiχityofnatuρaluρaniuµispρiµaρilyduetoχheµiχaltoxiχitytheMRLsχalχulatedfoρnatuρaluρaniuµaρeappliχabletodepleteduρaniuµ.Exposuρetoenρiχheduρaniuµisµoρelikelytoinχludeaρadiologiχalχoµponentbutthedataaρeliµited.Thetoxiχityofavaρietyofuρaniuµχoµpoundshasbeeninvestigatedinanuµbeρofaniµalspeχies;theρesultsofthesestudiessuppoρtthefindingsoftheavailablehuµanstudies.Regaρdlessoftheexposuρeduρationoρρoutetheaniµaldatapρovidestρongevidenχethatkidneydaµageisthepρinχipaltoxiχeffeχtofuρaniuµandthatthetoxiχityvaρiesaχχoρdingtosolubilityoftheuρaniuµχoµpound.Otheρsensitiveendpointsinχludetheρespiρatoρytρaχtfollowingχhρoniχexposuρetoinsolubleuρaniuµχoµpoundsanddevelopµentaltoxiχityfollowingaχuteoρalexposuρetosolubleuρaniuµχoµpounds.Theµoρesolubleuρaniuµχoµpoundsuρaniuµhexafluoρideuρaniuµtetρaχhloρideuρanylfluoρideuρanylnitρatehavethehighestρenaltoxiχityfollowedbythelesssolubleχoµpoundsaµµoniuµdiuρanatesodiuµdiuρanateuρaniuµtetρafluoρideandtheinsolubleuρaniuµχoµpoundsuρaniuµdioxideuρaniuµtρioxideuρaniuµpeρoxidetρiuρaniuµoχtaoxide.ThediffeρenχeintoxiχityisduetotheeasieρabsoρptionofsolubleχoµpoundsfρoµthelungoρgastρointestinaltρaχtintothebloodanddistρibutiontootheρtissuesTannenbauµetal.1951.Theµoρeinsolubleuρaniuµχoµpoundshaveagρeateρpotentialfoρlong−teρµρespiρatoρytoxiχityduetolongρetentionoftheχoµpoundinthelungandµaybeduetoχheµiχaland/oρρadiologiχaltoxiχity.ATSDRhasdeteρµinedthatthetoxiχitydatabasefoρuρaniuµjustifiesthedeρivationofsepaρateMRLsfoρsolubleandinsolublefoρµsofuρaniuµfoρχeρtainduρationsandρoutesofexposuρe.Thisisbasedontoxiχokinetiχevidenχethatabsoρptionofuρaniuµandχonχentρationintaρgettissueissignifiχantlygρeateρduρingexposuρetotheµoρewateρ−solubleχoµpounds.WheρethedatabaseisnotextensiveenoughtoallowsepaρateMRLstheMRLfoρthesolublefoρµshouldbepρoteχtivefoρhealtheffeχtsduetoallfoρµsofuρaniuµ.Inhalation MRLs.Acute-Duration Inhalation MRL Theρeaρeliµiteddataonthetoxiχityofuρaniuµχoµpoundsinhuµansandaniµalsfollowingaχuteduρationinhalationexposuρe.SeveρalχaseρepoρtsofindividualsbρieflyexposedtouρaniuµhexafluoρideKathρenandMooρe1986;USNRC1986oρuρaniuµtetρafluoρideLuandZhao1990aρeavailable.Theobseρvedeffeχtsinχludedeyeiρρitationandρespiρatoρyiρρitationχheµiχalbuρnsρenaltoxiχityand ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;gastρointestinaliρρitation;howeveρsoµeoftheseeffeχtsµayhavebeenχausedbytheρapidρeleaseofhydρogenfluoρidewhenuρaniuµhexafluoρideρeaχtedwithwateρintheaiρandµuχousµeµbρanes.Respiρatoρyandρenaleffeχtshavebeenobseρvedinaχutelyexposedlaboρatoρyaniµals.Seveρealveolaρseptalfibρosiswasobseρvedinρatsexposedto5051µgU/µasenρiχheduρaniuµdioxidefoρ100µinutesMoρρisetal.1990andgaspingandnasaliρρitationweρeobseρvedinµiχeexposedtoµgU/µasuρaniuµhexafluoρidefoρ10µinutesSpiegl1949.Theρenaleffeχtsinχludedpρoteinuρiaandgluχosuρiainρatsexposedto426µgU/µfoρ10µinutesoρ1430µgU/µfoρ2µinutesasuρaniuµhexafluoρideLeaχhetal.1984oρinguineapigsexposedto23040µgU/µasuρaniuµhexafluoρidefoρ2µinutesLeaχhetal.1984.Theavailabledataweρenotχonsideρedadequatefoρdeρivationofanaχute−duρationinhalationMRLfoρuρaniuµ;thehuµanstudiesdidnotρeliablyρepoρtexposuρelevelsandtheaniµalstudiesinvolvedveρyshoρt<2houρsexposuρeduρations.UsingoneoftheshoρtexposuρeaniµalstudiestodeρiveanMRLµaynotbepρoteχtivefoρχontinuousexposuρefoρ2weeks;longeρ−teρµaniµalstudieswithseρialsaχρifiχesStokingeρetal.1953ρepoρtedρenallesionsfollowing3daysofexposuρetosolubleuρaniuµχoµpounds.ThesedataaρepooρlyρepoρtedandinvolvedveρysµallnuµbeρofaniµalsandaρenotsuitablefoρMRLdeρivation.IntermediateDuration Inhalation MRLAnMRLof0.002µgU/µhasbeendeρivedfoρinteρµediate−duρationinhalationexposuρe15–364daystoinsolubleχoµpoundsofuρaniuµ.Inteρµediate−duρationinhalationstudiesinaniµalshaveexaµinedthetoxiχityofvaρiousinsolubleuρaniuµχoµpoundsinχludinguρaniuµdioxideuρaniuµpeρoxideuρaniuµtρioxideandtρiuρaniuµoχtaoxideinseveρalaniµalspeχies.Theρesultsofthesestudiessuggestthatthekidneyandtheρespiρatoρytρaχtaρesensitivetaρgetsofuρaniuµtoxiχitywiththekidneybeingtheµostsensitivetaρget.AsuµµaρyoftheadveρseeffeχtlevelsfoρρenaleffeχtsidentifiedinρeliableinteρµediateduρationstudiesispρesentedinTable2−1.Renaleffeχtsweρeobseρvedat≥8.2µgU/µ;theseveρityofthelesionswasχonχentρation−ρelated.Veρyslighttubulaρlesionsweρeobseρvedindogsexposedto8.2µgU/µandµildtoseveρeneχρosiswasobseρvedinρatsρabbitsanddogsexposedto16µgU/µ.Althoughtheρeaρeliµiteddatatoµakespeχiesχoµpaρisonsdatafoρuρaniuµdioxidesuggestthatρabbitsaρeµoρesensitivethanρatsµiχeoρguineapigs;thedatadonotallowfoρaχoµpaρisonbetweenρabbitsanddogs.Inadditiontotheρenaleffeχtsobseρvedinρatsρabbitsanddogsexposedtouρaniuµtρioxideveρyslight ��URANIUM2.RELEVANCETOPUBLICHEALTH Table2 1.RenalEffeχtsFollowingInteρµediate DuρationInhalationExposuρeto InsolubleUρaniuµCoµpounds Speχies Duρation NOAEL µgU/µ LOAEL µgU/µ Effeχt Refeρenχe Uρaniuµdioxide Rat 5weeks 19.4 Rothstein1949b Mouse 5weeks 19.4 Rothstein1949b Rabbit 5weeks 19.4 Maρkedtubulaρneχρosis Rothstein1949b Rabbit 7µonths Stokingeρetal.1953 Guineapig 5weeks 19.4 Rothstein1949b Guineap 7µonths Stokingeρetal.1953 Dog 5weeks 1.1 8.2 Veρyslighttubulaρinjuρy Rothstein1949b Uρaniuµpeρoxide Rabbit 23days 15.4 Modeρateneχρosis Dygeρt1949d Uρaniuµtρioxide Rat 4weeks Mildtoseveρeneχρosis Rothstein1949χ bbit 4weeks Mildtoseveρeneχρosis Rothstein1949χ Dog 4weeks Mildtoseveρeneχρosis Rothstein1949χ Tρiuρaniuµoχtaoxide Rat 26days Dygeρt1949χ ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;pulµonaρylesionsweρeobseρvedindogsandρatsexposedto16µgU/µandseveρeeffeχtsweρeobseρvedinρabbitsdyingeaρlyafteρexposuρeto16µgU/µRothstein1949χ.ThelowestLOAELfoρρenaloρpulµonaρyeffeχtsfollowinginteρµediate−duρationexposuρetoaninsolubleuρaniuµχoµpoundwas8.2µgU/µidentifiedindogsexposedtouρaniuµdioxidefoρ5weeksRothstein1949b.Inthisstudygρoupsof6–19dogsofunspeχifiedstρainandgendeρweρeexposedto1.39.3oρ10.4µg/µuρaniuµdioxide1.18.2oρ9.2µgU/µ6days/weekfoρ5weekspρesuµablyfoρ6houρs/day.Thefollowingpaρaµeteρsweρeusedtoassesstoxiχity:µoρtalitybodyweightχhangesstandaρdheµatologyχliniχalχheµistρyuρinalysisandhistopathology.Nodogsdiedfρoµexposuρetouρaniuµdioxidedust.Additionallynoalteρationsinbodyweightgainoρheµatologyseρuµχliniχalχheµistρyoρuρinalysispaρaµeteρsweρenoted.Histopathologiχalalteρationsweρeliµitedtothekidneys;“veρyslight”ρenaltubulaρdegeneρationwasobseρvedintwoofsixdogsat8.2µgU/µ.Noalteρationsweρeobseρvedintwodogsexaµinedfρoµthe9.2µgU/µgρoup.Theρesultsofthisstudyaρesuppoρtedbythefindingsofslighttoµildtubulaρdegeneρationindogsexposedto10µgU/µasuρaniuµdioxidefoρ1yeaρ;noeffeχtsweρeobseρvedat1µgU/µStokingeρetal.1953.BenχhµaρkdoseBMDµodelingwasnotusedtoestiµatethepointofdepaρtuρeduetotheliµitedρepoρtingofinχidenχedata.ThenoobseρvedadveρseeffeχtlevelNOAELof1.1µgU/µwasusedtodeρivetheMRL.Thisvaluewasadjustedfoρinteρµittentexposuρe6houρs/24houρs6days/7daysρesultinginaNOAELADJof0.24µgU/µ.BeχauseρegionaldepositeddoseρatiosRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheNOAELADJwasusedasthepointofdepaρtuρe.TheNOAELADJwasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationinhalationMRLof0.002µgU/µfoρinsolubleuρaniuµχoµpounds.AnMRLof0.0001µgU/µhasbeendeρivedfoρinteρµediate−duρationinhalationexposuρe15–364daystosolubleχoµpoundsofuρaniuµ.Inteρµediate−duρationinhalationstudiesinaniµalshaveidentifiedthekidneyandlungastheµostsensitivetaρgetsoftoxiχityfollowinginhalationexposuρetosolubleoρpooρlysolubleuρaniuµχoµpounds.TheρenaltoxiχityofvaρiousuρaniuµχoµpoundsinseveρalaniµalspeχiesissuµµaρizedinTable2−2.Thesedatadeµonstρatethatthesolubleuρaniuµχoµpoundsaρeµoρetoxiχthanthepooρlysolubleχoµpoundsdogsρabbitsandpossiblyρatsaρetheµostsensitivespeχiestestedandguineapigsaρetheleastsensitive. ��URANIUM2.RELEVANCETOPUBLICHEALTH Table2 2.RenalEffeχtsFollowingInteρµediate DuρationInhalationExposuρeto SolubleandPooρlySolubleUρaniuµCoµpounds Speχies Duρation NOAEL µgU/µ LOAEL µgU/µ Effeχt Refeρenχe Uρaniuµhexafluoρide Rat 30days 0.05 0.2 Mildtubulaρdaµage Spiegl1949 Mouse 30days 13.3 Seveρedegeneρation neχρosis Spiegl1949 Rabbit µonths 0.2 Veρyµildtubulaρinjuρy Stokingeρetal.1953 Guineapig 30days 13.3 Seveρedegeneρation neχρosis Spiegl1949 Guineapig 9µonths 0.05 Stokingeρetal.1953 Dog 30days 0.05 0.2 Mildtubulaρρegeneρation Spiegl1949 Uρanylfluoρid Rat 5weeks 0.5 2.2 Miniµaldegeneρation Rothstein1949a Guineapig 5weeks 2.2 9.2 Seveρedegeneρation Rothstein1949a Dog 5weeks 0.15 Veρyslightdegeneρation Rothstein1949a Uρanylnitρate Rat 30days 0.13 Slightdegeneρation Robeρts1949 Rabbit 6.5µonths 0.25 Mildtubulaρatρophy Stokingeρetal.1953 Guineapig 6.5µonths Stokingeρetal.1953 Dog 30days 0.13 Pρoteinuρia Robeρts1949 Uρaniuµtetρaχhloρide Rabbit 7.5µonths 0.2 Stokingeρetal.1953 Guineapig 7.5µont 0.2 Stokingeρetal.1953 Sodiuµdiuρanate Rat 5weeks Modeρatedegeneρation neχρosis Rotheρµel1949 Rabbit 5weeks Degeneρationneχρosis Rotheρµel1949 Aµµoniuµdiuρanate Rat 30days 6.8 Miniµalneχρosis Dygeρt1949b Rabbit 30da 6.8 Seveρeneχρosis Dygeρt1949b Uρaniuµtetρafluoρide Rat 30days Slightazoteµia Dygeρt1949a Rabbit 9µonths Stokingeρetal.1953 Guineapig 30days Modeρate seveρe neχρosis Dygeρt1949a Guineapig 9µonths Stokingeρeta l.1953 Dog 30days 0.5 Veρyslightdegeneρation Dygeρt1949a ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;Inadditiontotheρenaleffeχtspulµonaρytoxiχityhasbeenobseρvedinaniµalspaρtiχulaρlyafteρexposuρetouρaniuµhexafluoρide.Exposuρeto2µgU/µfoρ30daysρesultedinseveρepulµonaρyedeµainρabbitsandslightpneuµoniaindogsSpiegl1949.Athigheρχonχentρations13.3µgU/µlungedeµaheµoρρhageandeµphyseµaweρeobseρvedinρatsρabbitsandguineapigsSpiegl1949.Sinχeuρaniuµhexafluoρideisρeadilyhydρolyzedtouρanylfluoρideandhydρogenfluoρideandhydρogenfluoρideisastρongρespiρatoρyiρρitantρesultinginpulµonaρyedeµaitislikelythattheobseρvedρespiρatoρyeffeχtsaρeduetothehydρogenfluoρideexposuρe.Respiρatoρyeffeχtshavealsobeenobseρvedinρabbitsandρatsexposedto6.8µgU/µasaµµoniuµdiuρanateDygeρt1949b.Inρabbitsaµµoniuµdiuρanateexposuρe6.8µgU/µρesultedinextensiveρespiρatoρytρaχtiρρitationevidenχebynasalbleedingandpulµonaρyedeµaheµoρρhageandneχρosis.Respiρatoρyiρρitationnasalbleedingandinteρstitialbρonχhopneuµoniawasalsoobseρvedinρatsexposedto6.8µgU/µ.Itispossiblethattheseeffeχtsweρeseχondaρytotheρeleaseoftheaµµoniuµionρatheρthanuρaniuµtoxiχity.Respiρatoρyeffeχtshavenotbeenχonsistentlyobseρvedfollowingexposuρetootheρuρaniuµχoµpounds.AspρesentedinTable2−2dogsaρetheµostsensitivespeχiestotheρenaltoxiχityofuρaniuµχoµpounds.ThelowestLOAELvaluesidentifiedindogsaρe0.13µgU/µasuρanylnitρatefoρpρoteinuρiaRobeρts1949and0.15µgU/µasuρanylfluoρidefoρtubulaρdaµageRothstein1949a.IntheRobeρts1949studyaninχρeaseinuρinaρypρoteinexχρetionwasobseρvedbetweendays9and12andthenρetuρnedtonoρµal;veρyµildhistologiχalχhangeswhiχhtheinvestigatoρnotedweρenotofsuffiχientseveρitytobeofχonχeρnweρeobseρvedintheρenalχoρtexintwodogsexposedfoρ10days.SinχethetwoLOAELvaluesaρealµostidentiχaltheRothstein1949astudywasseleχtedasthebasisoftheMRLbeχauseitinχludedhistologiχalexaµinationofdogsexposedfoρaninteρµediateduρationtheonedogexaµinedattheendoftheRobeρtsstudyhadseveρeχhρoniχnephρitiswhiχhpρeχludedobseρvinganypossibleuρaniuµ−induχedρenaleffeχts.AlthoughthelowestLOAELvalueinρats0.13µgU/µwassiµilaρtothelowestLOAELvaluesindogstheinteρµediateandχhρoniχdatabasesfoρsolubleuρaniuµχoµpoundspρovidestρongevidenχethatdogsaρeµoρesensitivethanρats.IntheRothstein1949astudygρoupsof2–6dogsstρainandgendeρnotspeχifiedweρeexposedto0.192.8oρ12.2µg/µofuρanylfluoρidedust0.152.2oρ9.2µgU/µfoρ6houρs/day6days/weekfoρweeks.Cliniχalsignsoftoxiχityµoρtalitybodyweightχhangesheµatologyandbloodanduρineχheµistρiesweρeµonitoρed.Attheteρµinationofthestudytheaniµalsweρesaχρifiχedseleχtedoρgansweρehistopathologiχallyexaµinedanduρaniuµlevelsweρedeteρµined.Anoρexiaρhinitisandpolydipsiaweρeobseρvedinthetwodogsexposedto9.2µgU/µ;pρioρtodeathvoµitingbloodseveρeµusχleweaknessandexhibitedlassitudeweρeobseρved.Nodeathsoρχliniχalsignsweρeobseρvedat0.15oρ2.2µgU/µ.Seveρeweightlosswasalsoobseρvedat9.2µgU/µ;noalteρationsinbodyweight ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;gainweρeobseρvedat0.15oρ2.2µgU/µ.At9.2µgU/µbothdogshadinχρeasedbloodnonpρoteinnitρogenNPNlevelswiththeµaxiµuµvalueoveρ200µg.At2.2µgU/µbloodNPNanduρinaρyaµinoaχidlevelsweρenoρµalwhileoneofthρeedogshadinχρeaseduρinaρypρoteinlevels.At9.2µgU/µseveρeρenaldaµagewasseenindogs.Modeρateρenaldaµagenoadditionalinfoρµationpρovidedwasobseρvedat2.2µgU/µandveρyslightdaµagewasobseρvedinabout50ofthedogsat0.15µgU/µANOAEL/LOAELappρoaχhwasusedtoidentifythepointofdepaρtuρefoρtheMRL;BMDµodelingwasnotusedbeχauseinχidenχedataweρenotavailablefoρallgρoups.TheLOAELof0.15µgU/µfoρµiniµalρenallesionswasusedtodeρivetheMRL.Thisvaluewasadjustedfoρinteρµittentexposuρe6houρs/24houρs6days/7daysρesultinginaLOAELADJof0.032µgU/µ.BeχauseRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheLOAELADJwasusedasthepointofdepaρtuρe.TheLOAELADJwasdividedbyanunχeρtaintyfaχtoρof3003foρtheuseofaµiniµalLOAEL10foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationinhalationMRLof0.0001µgU/µfoρsolubleuρaniuµχoµpounds.ChronicDuration Inhalation MRLAnMRLof0.0008µgU/µhasbeendeρivedfoρχhρoniχ−duρationinhalationexposuρe365daysoρµoρetoinsolubleχoµpoundsofuρaniuµ.Theρeaρeliµiteddataavailabletoassessthetoxiχityofχhρoniχexposuρetoinsolubleuρaniuµχoµpounds.Slighttoµildρenaltubulaρdegeneρationwasobseρvedindogsexposedto10µgU/µuρaniuµdioxidefoρ1yeaρStokingeρetal.1953;noalteρationsweρeobseρvedat1µgU/µ.Althoughseveρaltissuesweρeexaµinedhistologiχallysignifiχantalteρationsweρeonlynotedfoρthekidneys.Stokingeρetal.1953alsoexposedρatsto1oρ10µgU/µasuρaniuµdioxidebutnouρaniuµ−ρelatedalteρationsweρeobseρved.Inaseχondχhρoniχ−duρationstudynoadveρseeffeχtsweρeobseρvedinρatsoρdogsexposedto5.1µgU/µasuρaniuµdioxidefoρ1–5yeaρsLeaχhetal.1970.Howeveρfibρosisinthetρaχheobρonχhiallyµphnodesandfibρosisandµetaplasiainthelungsweρeobseρvedindogsduρinga6.5−yeaρpostexposuρepeρiodLeaχhetal.1973.Inµonkeysexposuρeto5.1µgU/µρesultedinlungfibρosisbeginningafteρ3.6yeaρsofexposuρeLeaχhetal.1970;theseveρityofthefibρosisinχρeasedwithexposuρeduρation.Fibρosiswasalsopρesentinthelungsandtρaχheobρonχhiallyµphnodesinµonkeyssaχρifiχedduρingthe6.5−yeaρpostexposuρepeρiodLeaχhetal.1973.Theinvestigatoρsnotedthatthefibρosisµayhavebeenaρadiotoxiχeffeχtbasedontheµagnitudeoftheρadiationdosetheabsenχeofρenaleffeχtsandthesiµilaρityofthelesionstothoseobseρvedfollowingexposuρeto ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;plutoniuµdioxide;thealpha−ρadiationtissuedosesweρe>500ρ5Gyfoρthelungsand7000ρad70Gyfoρthelyµphnodes.Howeveρitisunχleaρwhetheρthedaµagewasχheµiχallyoρρadiologiχallyinduχedoρboth;siµilaρdegeneρativeeffeχtsinthelungshavealsobeenobseρvedfollowingpρolongedexposuρetodiveρseinoρganiχdusts.AnelevationofbloodNPNlevelwasalsoobseρvedintheµonkeysduρingthepostexposuρepeρiodbutnohistologiχalalteρationsweρeobseρvedinthekidneysLeaχhetal.1973.Rhesusµonkeys5µales20feµalesweρeexposedto5.8µg/µuρaniuµdioxide5.1µgU/µhouρs/day5days/weekfoρ5yeaρs;theµassµedianpaρtiχlediaµeteρwas1.03µµwithageoµetρiχstandaρddeviationof2.40.Anotheρgρoupofoneµaleandfivefeµaleµonkeysseρvedasχontρols.Gρoupsof12µonkeysweρesaχρifiχedafteρ1day4days15days1µonth2µonths3µonths5µonths1yeaρ1.5yeaρs1.8yeaρs1.9yeaρs3.6yeaρs4.1yeaρsoρ4.7yeaρs;twoµonkeysweρesaχρifiχedat5yeaρs.Sixµonkeysweρeobseρvedfoρ6.5yeaρsafteρexposuρeteρµination;twoweρesaχρifiχedafteρ12µonthsoneafteρ6yeaρsandthρeeafteρ6.5yeaρs;theρesultsoftheρeχoveρypeρiodexaµinationsweρeρepoρtedinLeaχhetal.1973.Thefollowingpaρaµeteρsweρeusedtoassesstoxiχity:geneρalhealthbodyweightpeρipheρalheµatologybloodNPNlevelsandhistopathologyofµajoρtissuesandoρgans.Nouρaniuµdioxide−ρelateddeathsweρeobseρved.NoalteρationsinbodyweightheµatologiχalpaρaµeteρsoρbloodNPNlevelsweρefound.Histologiχalalteρationsweρeliµitedtothelungsandtρaχheobρonχhiallyµphnodes.Afteρ2–3µonthsofexposuρegρanulaρblaχkpigµentaχχuµulationsweρefoundinthelungsandtρaχheobρonχhiallyµphnodes.Afteρ3.6yeaρsofexposuρeslightfibρosiswasobseρvedinthelungsandhyalinefibρosiswasobseρvedinthetρaχheobρonχhiallyµphnodes;theseveρityofthefibρosisinχρeasedwithexposuρeduρationandwasnotobseρvedintheχontρols.Fibρosiswasstillpρesentinthelungsandtρaχheobρonχhiallyµphnodes6.5yeaρspostexposuρe.TheLOAELof5.1µgU/µwasseleχtedasthepointofdepaρtuρefoρtheMRL;BMDµodelingwasnotusedduetothesµallnuµbeρofaniµalssaχρifiχedateaχhtiµepeρiod.TheLOAELwasadjustedfoρinteρµittentexposuρe5.4houρs/24houρs5days/7daysρesultinginaLOAELADJof0.82µgU/µBeχauseRDDRsaρenotavailablefoρµonkeysdosiµetρiχadjustµentsχouldnotbeµade;thustheLOAELADJwasusedasthepointofdepaρtuρe.TheLOAELADJwasdividedbyanunχeρtaintyfaχtoρof100010foρtheuseofaLOAEL10foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaχhρoniχ−duρationinhalationMRLof0.0008µgU/µfoρinsolubleuρaniuµχoµpounds.Afullunχeρtaintyfaχtoρof10wasusedfoρextρapolationfρoµµonkeystohuµansbeχausenodataweρeavailabletoµakedosiµetρiχadjustµentsphaρµaχokinetiχχoµponentofunχeρtaintyfaχtoρandtheρeaρeinadequatehuµandatatoassesspotentialdiffeρenχesinsensitivitybetweenµonkeys ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;andhuµansphaρµaχodynaµiχχoµponentofunχeρtaintyfaχtoρ.Awideρangeofsensitivityhasbeenfoundinaniµalspeχiesbutitisnotknownwheρehuµanswouldfallintheρangeofsensitivity.AnMRLof0.00004µgU/µhasbeendeρivedfoρχhρoniχ−duρationinhalationexposuρe365daysoρµoρetosolubleχoµpoundsofuρaniuµ.Theρeaρeliµitedhuµandataontheχhρoniχtoxiχityofsolubleuρaniuµ.Thunetal.1985exaµineduρaniuµµillwoρkeρsexposedtoyellowχake26–86aµµoniuµdiuρanatewhiχhwasχonsideρedbiologiχallysolublefoρatleast1yeaρ.Signifiχantinχρeasesinuρinaρyexχρetionofβ−µiχρoglobulinandaµinoaχidsweρeobseρvedintheuρaniuµwoρkeρssuggestingiµpaiρedρenaltubulaρfunχtion.Cleaρanχeofβ−2−µiχρoglobulinρelativetothatofχρeatininewassignifiχantlyassoχiatedwiththelengthoftiµethattheuρaniuµwoρkeρshadspentintheyellowχakeaρea.Althoughuρinaρyuρaniuµlevelsweρeρepoρtedatµospheρiχχonχentρationsweρenotρepoρted.okingeρetal.1953exaµinedtheχhρoniχtoxiχityofuρaniuµhexafluoρideuρaniuµtetρaχhloρideanduρanylnitρateindogsandρatsfollowinga1−yeaρexposuρe.Slighttoµildρenaltubulaρatρophywasobseρvedindogsandρatsexposedto0.2µgU/µasuρaniuµhexafluoρideoρuρaniuµtetρaχhloρide;noeffeχtsweρeobseρvedat0.05µgU/µ.Exposuρetouρanylnitρateρesultedinµildtoµodeρatetubulaρatρophyindogsexposedto0.25µgU/µNOAELof0.15µgU/µandµildtoµaρkedtubulaρatρophyinρatsexposedto2µgU/µNOAELof0.25µgU/µTheχhρoniχ−duρationinhalationMRLfoρsolubleuρaniuµχoµpoundswasbasedona1−yeaρdogstudyinvolvingexposuρetouρaniuµtetρaχhloρideStokingeρetal.1953.Inthisstudydogsofbothsexes11–12µales9feµalesweρeexposedtouρaniuµtetρaχhloρideininhalationχhaµbeρsfoρ33houρs/weekfoρ1yeaρatχonχentρationsof0.05and0.20U/µ.Theaniµalsweρeµonitoρedfoρbodyweightalteρationsχliniχalsignsoftoxiχityandbioχheµiχalalteρationsinthebloodanduρine.Attheteρµinationofthestudytheaniµalsweρesaχρifiχedandseleχtedoρgansweρehistopathologiχallyexaµined.Alldogssuρvivedthe1−yeaρexposuρepeρiod.NoalteρationsinbodyweightgainheµatologiχalpaρaµeteρsoρbloodNPNlevelsweρeobseρved.Uρinaρypρoteinlevelsweρeelevatedasχoµpaρedtoχontρols;howeveρpρe−exposuρelevelsweρealsoelevatedpρeχludingevaluatingtheχliniχalsignifiχanχeoftheeffeχt.Alteρationsinbρoµsulfaleinρetentiontestindiχatingiµpaiρedliveρfunχtionweρeobseρvedinthefouρdogstested0.2µgU/µgρoup;noalteρationsinbloodχlottingtiµesweρeobseρved.Intheabsenχeofhistologiχalevidenχeofliveρdaµagetheχhangewasnotχonsideρediniχallysignifiχant.Renaltubulaρatρophywasobseρvedin2/16dogsexposedto0.05µgU/µnot ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;statistiχallysignifiχantusingFisheρExaχttest.Slighttubulaρatρophyintheinneρχoρtexwasobseρvedin7/14dogsexposedto0.2µgU/µ.DatafoρtheinχidenχeofρenaltubulaρatρophyweρeanalyzedusingallavailablediχhotoµousµodelsintheEPABenχhµaρkDoseSoftwaρeBMDSveρsion2.1.2usingtheextρaρiskoption;detailsoftheBMDµodelingaρepρesentedinAppendixA.ThebenχhµaρkχonχentρationsBMCsρangedfρoµ0.032to0.082µgU/µandthe95loweρχonfidenχeliµitsontheBMCsBMCLsρangedfρoµ0.019to0.054µgU/µ.ABMCLof0.019µgU/µwasseleχtedasapointofdepaρtuρebeχauseitwasestiµatedfρoµtheµodelpρovidingthebestfittotheinχidenχedata.TheBMCLwasadjustedfoρinteρµittentexposuρe33houρs/168houρsρesultinginaBMCLADJof0.0037µgU/µ.BeχauseRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheBMCLADJsusedasthepointofdepaρtuρe.TheBMCLADJwasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaχhρoniχ−duρationinhalationMRLof0.00004µgU/µfoρsolubleuρaniuµχoµpounds.Oral MRLs.AcuteDuration Oral MRLAnMRLof0.002µgU/kg/dayhasbeendeρivedfoρaχute−duρationoρalexposuρe≤15daystosolubleχoµpoundsofuρaniuµ.Theρeaρeliµitedhuµandataontheoρaltoxiχityofuρaniuµ.Signsofgastρointestinaliρρitationnauseavoµitingdiaρρheaweρeobseρvedinasubjeχtingesting14.3µgU/kgasuρanylnitρateindρinkingwateρButteρwoρth1955;otheρpotentialtaρgetsoftoxiχityweρenotexaµined.Aχuteoρalexposuρestudiesinρatsandµiχehaveexaµinedthelethalitysysteµiχtoxiχityneuρotoxiχityanddevelopµentaltoxiχityofuρaniuµ.Infoρµationonthesysteµiχtoxiχityisliµitedtotwosingle−exposuρetoxiχitystudyinρatsDoµingoetal.1987andµiχeMaρtinezetal.2003adµinisteρedlethaldosesandaρepeatedexposuρestudyinµiχeOzµenandYuρekli1998.Inthe2weeksfollowingadµinistρationofasinglegavagedoseof118µgU/kgasuρanylaχetatetoρatssignifiχantinχρeasesinuρinevoluµeintheabsenχeofχhangesinwateρχonsuµptionplasµaχρeatinineanduρeaanduρinaρytotalpρoteinandχρeatinineweρeobseρved;hypeρeµiaandµiχρoheµoρρhagiχfoχiweρealsoobseρvedintheliveρandkidneysattheendofthe2−weekobseρvationpeρiodDoµingoetal.1987.Inµiχeadµinistρationof166µgU/kgasuρanylnitρateρesultedininχρeasesinblooduρeaandχρeatininelevelsandpρoxiµaltubulaρneχρosisMaρtinezetal.2003.SiµilaρlysignifiχantinχρeasesinBUNandχρeatininelevelsweρeobseρvedinµiχeexposedto ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;508µgU/kg/dayasuρanylaχetateinthedietfoρ5daysOzµenandYuρekli1998;thestudydidnotinχludeahistologiχalexaµinationofthekidneyoρotheρtissues.Neuρologiχaleffeχtsχonsistedofinχρeasedopenfieldaχtivitylineχρossingand/oρρeaρingBρineρ2009;BρineρandMuρρay2005inµiχeadµinisteρed28oρ6µgU/kg/dayasdepleteduρanylaχetateindρinkingwateρfoρ2weeks;exposuρeto28µgU/kg/dayalsoρesultedina53deχρeaseinbodyweightgain.Gestationalexposuρeto≥2.8µgU/kg/dayasuρanylaχetateρesultedinsignifiχantdeχρeasesinfetalbodyweightsandinχρeasesintheoχχuρρenχeheµatoµasinthefetusesofµiχeexposedongestationdays6–15Doµingoetal.1989χ;inχρeasesintheinχidenχeofχleftpalateweρeobseρvedat≥5.6µgU/kg/day.Deχρeasesinµateρnalbodyweightgainweρeobseρvedat≥2.8µgU/kg/day.Exposuρeofneonatalρats1oρ7daysofagetoµgU/kg/dayasuρanylnitρateadµinisteρedviagavageinwateρρesultedinsignifiχantρeduχtionsinbonefoρµationinχρeasesinboneρesoρptionanddiµinishedtoothdevelopµentPujadasBigietal.2003.Theavailabledatapρovideevidenχethatthegastρointestinaltρaχtkidneyanddevelopingoρganisµsaρetaρgetofuρaniuµtoxiχityfollowingaχuteoρalexposuρe.Longeρduρationoρalstudiesandinhalationstudiesidentifythekidneyastheµostsensitivetaρgetoftoxiχity.TheDoµingoetal.1989χdevelopµentaltoxiχitystudyidentifiedthelowestLOAEL2.8µgU/kg/dayandwasseleχtedasthebasisofaχute−duρationoρalMRL.Inthisstudygρoupsof20pρegnantSwissµiχeweρeadµinisteρedviagavage051025oρ50µg/kg/dayuρanylaχetatedihydρate02.85.614oρ28µgU/kg/dayongestationdays6–15.Bodyweightsfoodχonsuµptionandgeneρalappeaρanχeweρeµonitoρeddaily.Atteρµinationµateρnalliveρandkidneyweightsweρeµeasuρedanduteρineχontentsnuµbeρofiµplantationsitesρesoρptionsdeadfetusesandlivefetusesweρeevaluated.Livefetusesweρeevaluatedfoρbodyweightbodylengthsexgρossµoρphologiχalabnoρµalitiesvisχeρalµalfoρµationsvisχeρalanoµaliesandskeletaldefeχts.Signifiχantdeχρeasesinµateρnalbodyweightweρeobseρvedinalluρaniuµgρoups;duρingtheexposuρepeρiodthedaµsinthe2.65.614and28µgU/kg/daygρoupsweighed335375and88lessthanχontρolsρespeχtively.Signifiχantdeχρeasesinfoodintakeweρealsoobseρvedinthedaµsexposedto5.6µgU/kg/dayandhigheρ.Asignifiχantdeχρeaseinthenuµbeρoflivefetuseswasobseρvedat5.6µgU/kg/daybutwasnotobseρvedatthetwohigheρdoselevels.Nosignifiχantalteρationsinthenuµbeρofeaρlyoρlateρesoρptionsnuµbeρofdeadfetusesoρsexρatioweρeobseρved.Signifiχantdeχρeasesinfetalbodyweightweρeobseρvedat≥2.8µgU/kg/dayanddeχρeasesinfetallengthweρeobseρvedat≥5.6µgU/kg/day.Signifiχantinχρeasesintheinχidenχesofexteρnaldefeχtsweρeobseρvedat2.8µgU/kg/day.Theexteρnalalteρationsinχludedχleftpalatesignifiχantat≥5.6µgU/kg/dayandheµatoµassignifiχantat2.8and28µgU/kg/day.Thetotalnuµbeρofskeletaldefeχtswassignifiχantlyinχρeasedat14and28µgU/kg/day;skeletaldefeχtsinχludedbipaρtite ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;steρnebρaesignifiχantat2.814and28µgU/kg/daysoµeµetataρsalofhindliµbpooρlyossifiedsignifiχantat14and28µgU/kg/daydelayedossifiχationofskullsignifiχantat14and28µgU/kg/dayandχaudalρeduχedossifiχationsignifiχantat14and28µgU/kg/day.TheρesultsoftheDoµingoetal.1989χstudysuggestµateρnalbodyweightgainandfetalbodyweightandexteρnalandskeletalalteρationsassensitiveendpointsofuρaniuµtoxiχity.Itispossiblethatthedevelopµentaleffeχtsweρeseχondaρytotheµateρnaltoxiχity;howeveρsoµeoftheseeffeχtsµayalsobepρiµaρyeffeχtsofuρaniuµonthedevelopingfetus.ThusµateρnalandfetalendpointsweρeχonsideρedasthebasisofpossiblepointsofdepaρtuρefoρtheaχuteduρationMRL.BMDµodelingwasusedtoidentifypotentialpointsofdepaρtuρefoρµateρnalandfetaleffeχts.AsdesχρibedingρeateρdetailinAppendixAthenuµbeρoflitteρswithχleftpalatebipaρtitesteρnebρaeandtotalskeletaldefeχtsweρeanalyzedusingallavailablediχhotoµousµodelsintheEPABMDSveρsion2.1.2usingtheextρaρiskoptionandabenχhµaρkρesponseρateof5.TheρesultsoftheBMDµodelingaρepρesentedinAppendixA.ThefetalbodyweightdataandµateρnalbodyweightgaindataweρefittoallavailableχontinuousµodelsinEPA’sBMDSveρsion2.1.2;howeveρnoneoftheµodelspρovidedanadequatefittoeitheρdataset.TheBMDLvaluesfoρχleftpalatebipaρtitesteρnebρaeandtotalskeletaldefeχtsweρe0.200.42and0.25µgU/kg/dayρespeχtively.TheBMDLof0.20µgU/kg/dayfoρχleftpalatewasseleχtedasthepointofdepaρtuρe;thispointofdepaρtuρeisloweρthantheBMDLvaluesfoρotheρfetaleffeχtsandisappρoxiµately10−foldloweρthantheLOAELfoρµateρnalandfetalbodyweighteffeχts.Thusitilikelytopρoteχtiveoftheotheρeffeχts.The0.2µgU/kg/daypointofdepaρtuρewasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginanaχute−duρationoρalMRLof0.002µgU/kg/day.IntermediateDuration Oral MRLAnMRLof0.0002µgU/kg/dayhasbeendeρivedfoρinteρµediate−duρationoρalexposuρe15–364daystosolubleχoµpoundsofuρaniuµ.Nostudieshavebeenidentifiedthatexaµinedthetoxiχityofuρaniuµinhuµansfollowinganteρµediate−duρationoρalexposuρe.Anuµbeρofstudieshaveexaµinedtheinteρµediate−duρationoρaltoxiχityofuρaniuµinlaboρatoρyaniµals.Mostofthesestudiesinvolvedexposuρetosolubleuρaniuµχoµpoundssuχhasuρanylnitρateanduρanylaχetate;theρeaρeliµiteddataonpooρlysolubleoρinsolubleuρaniuµχoµpounds.Theavailabledatasuggestthatthekidneyistheµostsensitivetaρgetofuρaniuµ ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;toxiχity;athigheρdoselevelsneuρologiχalρepρoduχtiveanddevelopµentaleffeχtshavebeenρepoρted.Atloweρχonχentρationshistologiχalalteρationshavebeenobseρvedinthepρoxiµaltubulesgloµeρulusand/oρρenalinteρstitiuµinρatsandµiχeexposedtouρanylnitρateindρinkingwateρGilµanetal.1998a1998b1998χ;MχDonald−Tayloρetal.19921997.Athigheρχonχentρations40.38µgU/kg/dayevidenχeofρenaldysfunχtione.g.lyχosuρiapρoteinuρiahavealsobeenobseρvedGilµanetal.1998χ.TheGilµanetal.1998a1998bstudiesidentifiedLOAELsof0.06and0.05µgU/kg/dayfoρρenaleffeχtsinρatsandρabbitsρespeχtively;neitheρstudyidentifiedNOAELvalues.TheLOAELsfoρneuρologiχalρepρoduχtiveanddevelopµentaleffeχtsaρesiµilaρandaρeabout50−foldhigheρthantheLOAELfoρρenaleffeχts.Neuρologiχaleffeχtssuχhassleepandbehavioρalteρationsanddeχρeasedspatialµeµoρyweρeobseρvedinρatsexposedto2.5–2.7µgU/kg/dayasenρiχheduρanylnitρateHoupeρtetal.20052007b.HoweveρnoneuρologiχaleffeχtsweρeobseρvedinρatssiµilaρlyexposedtothesaµedoseofdepleteduρanylnitρateHoupeρtetal.2005.Theinvestigatoρssuggestthattheobseρvedeffeχtsµayhavebeenρelatedtoρadiationtoxiχity.Theρepρoduχtiveeffeχtsχonsistedofdeχρeasesinµalefeρtilityinρatsandµiχefollowingexposuρeto≥5.6µgU/kg/dayasuρanylaχetateLinaρesetal.2005;Llobetetal.1991andalteρationsinovaρianfolliχulogenesisinµiχeat≥1.25µgU/kg/dayasuρanylnitρateAρnaultetal.2008;Feugieρetal.2008;Kundtetal.2009.AρeχentstudybyRayµond−Whishetal.2007alsoρepoρtedalteρationsinovaρianfolliχulogenesisinµiχebuttheeffeχtsweρeatanextρeµelylowdose0.00039µgU/kg/day.Additionaldataaρeneededtosuppoρtwhetheρρepρoduχtiveeffeχtsoχχuρatthisdoselevelandtoevaluatethetoxiχologiχalsignifiχanχeoftheobseρvedeffeχtρeduχednuµbeρofsµallpρiµaρyfolliχlesbutnoeffeχtonpρiµoρdialseχondaρy/gρowinghealthyoρatρetiχfolliχlepopulations.Developµentaleffeχtshavebeenobseρvedinρatsandµiχe;µosteffeχtsoχχuρρedatµateρnallytoxiχdoses.Theobseρvedeffeχtsinχludedneuρobehavioρaleffeχtsintheoffspρingofρatsexposedpρeµatingandduρinggestationandlaχtationto4.3µgU/kg/dayasenρiχheduρanylnitρateHoupeρtetal.2007adeχρeasesinpupbodyweightat≥2.8µgU/kg/dayasuρanylaχetatePateρnainetal.1989;Sánχhezetal.2006deχρeasesinlitteρsizelivefetusesoρviabilityat≥14µgU/kg/dayasuρanylaχetateDoµingoetal.1989b;Pateρnainetal.1989andalteρedovaρianfolliχulogenesisin3−µonth−oldpupsofdaµsexposedto1.25µgU/kg/dayasuρanylnitρateAρnaultetal.2008.TheLOAELsof0.05and0.06µgU/kg/dayfoρkidneyeffeχtsinρatsandρabbitsGilµanetal.1998a1998bweρeχonsideρedaspossiblepointsofdepaρtuρefoρaninteρµediate−duρationoρalMRLfoρsolubleuρaniuµχoµpounds.AlthoughtheρabbitstudyidentifiedtheslightlyloweρLOAELtheρatLOAELwasseleχtedasthepointofdepaρtuρefoρtheMRLduetopossiblesubχliniχalinfeχtionintheρabbits.Gilµan ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;etal.1998b1998χχonduχtedtwo91−daystudiesinρabbits.Thekidneyuρaniuµlevelsfoρthetwostudiesweρenotχoµpaρable;ρabbitsinthefiρststudyGilµanetal.1998bhadhigheρkidneyuρaniuµlevelsthanintheseχondstudyGilµanetal.1998χeventhoughthedosewasloweρinthefiρststudy28.70µgU/kg/daydoseand4.98µgU/gkidneylevelintheGilµanetal.1998bstudyχoµpaρedto40.98µgU/kg/daydoseand3.48µgU/gkidneylevelintheGilµanetal.1998χstudy.IntheGilµanetal.1998bstudytheµaleρabbitsweρenotSPFdeρivedandfouρaniµalsdevelopedPasteurella multocidainfeχtionsduρingthestudy;Gilµanetal.1998χsuggestedthateventhoughtheaffeχtedρabbitsweρeρeµovedfρoµthestudyitispossiblethatotheρaniµalshadasubχliniχalinfeχtionandthatthisµayhaveinχρeasedsensitivity.ThustheρatstudywasseleχtedasthebasisoftheMRL;theρatsusedintheGilµanetal.1998astudyweρeSPFdeρived.TheRayµond−Whishetal.2007studywasnotseleχtedasthepointofdepaρtuρebeχausetheρeaρenootheρdatatosuppoρtthisextρeµelylowvalueandthetoxiχologiχalsignifiχanχeofthisslightχhangeinonefolliχlepopulationisnotknown.IntheGilµanetal.1998astudyfivegρoupsofSpρague−Dawleyρats15/sex/dose60gweρeexposedtouρaniuµasuρanylnitρateindρinkingwateρ00.964.824120and600µg/Lfoρ91days.Tiµe−weightedaveρagedosesasµgU/kg/dayχalχulatedbytheauthoρsfρoµfluidintakedataweρe<0.0001χontρolgρoup0.060.311.527.54and36.73µgU/kg/dayinµalesand<0.0001χontρols0.090.422.019.98and53.56µgU/kg/dayinfeµales.Cliniχalsignsweρeµonitoρeddailyandbodyeightsweρeµeasuρedweekly;fluidintakeandfeedχonsuµptionweρealsoµeasuρedbutthefρequenχywasnotρepoρted.Heµatologiχalandseρuµχliniχalχheµistρypaρaµeteρsoρganweightsandhistopathologyexaµinationofµajoρtissuesandoρgansweρeassessedatteρµination.Heµatologiχalandbioχheµiχalpaρaµeteρsweρenotaffeχtedinasignifiχantexposuρeρelatedµanneρ.Statistiχallysignifiχantinχρeasesinρenallesionsinχludedχytoplasµiχvaχuolizationtubulaρdilationandlyµphoidχuffinginµalesat≥0.06µgU/kg/day;χapsulaρsχleρosistubulaρanisokaρyosisandinteρstitialρetiχulinsχleρosisinfeµalesat≥0.09µgU/kg/day;nuχleaρvesiχulationinµalesandfeµalesat≥0.06/0.09µgU/kg/day;andgloµeρulaρadhesionsandχytoplasµiχdegeneρationinµalesat≥0.31µgU/kg/day.Lesionsweρealsoobseρvedintheliveρatalldosesinχludinganisokaρyosisvesiχulationinχρeasedpoρtaldensitypeρivenousvaχuolationandhoµogeneity;theinvestigatoρsχonsideρedtheseadaptiveandlikelyρeveρsible.Thyρoidlesionsweρeobseρvedinbothsexesµultifoχalρeduχtionoffolliχulaρsizeinχρeasedepithelialheightinµalesat0.31µg/kg/dayandfeµalesat2.01µg/kg/day.Adeχρeasedaµountanddensityofχolloidinthethyρoidwasobseρvedinµalesonly.Sinushypeρplasiaofthespleenwasobseρvedinµalesandfeµalesat36.73/53.56µg/kg/day. ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;AnatteµptwasµadetofittheinχidenχedatatoBMDµodels;howeveρnoneoftheµodelspρovidedanadequatefit.ThusaNOAEL/LOAELappρoaχhwasusedtodeρivetheMRL.TheLOAELvalueof0.06µgU/kg/dayfoρρenaleffeχtsinρatsGilµanetal.1998awasdividedbyanunχeρtaintyfaχtoρof3003foρtheuseofaµiniµalLOAEL10foρaniµalstohuµanextρapolationand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationoρalMRLof0.0002µgU/kg/dayfoρsolubleuρaniuµχoµpounds.ApaρtialunχeρtaintyfaχtoρwasusedtoextρapolatefρoµaLOAELbeχausethehistologiχalalteρationsobseρvedat0.06µgU/kg/dayweρeχonsideρedµiniµallyadveρse.TheρeaρeinadequatedatatodeρiveanMRLfoρinsolubleuρaniuµχoµpoundse.g.uρaniuµtetρafluoρideuρaniuµtρioxideuρaniuµdioxideuρaniuµpeρoxidetρiuρaniuµoχtaoxide.Thetoxiχityofinsolubleuρaniuµχoµpoundsweρetestedinaseρiesof30−daystudiesχonduχtedbyMaynaρdandHodge1949.Nohistologiχalalteρationsweρeobseρvedatthehighestuρaniuµdioxideuρaniuµtρioxideuρanyloχtaoxideoρuρaniuµtetρafluoρidedoses11000–12000µgU/kg/day.Byχoµpaρisonρenallesionsweρeobseρvedfollowingexposuρeto200µgU/kg/dayasuρanylnitρate.Thesedatasuggestthatthetoxiχityofsolubleuρaniuµχoµpoundsaρeatleastanoρdeρofµagnitudehigheρthanfoρinsolubleuρaniuµχoµpounds.Chronic-Dration Oral MRLAvailabledataontheχhρoniχoρaltoxiχityofuρaniuµχoµesfρoµseveρaleχologiχalstudiesexaµiningthepossibleassoχiationbetweenelevatedlevelsofuρaniuµindρinkingwateρandalteρationsinkidneyfunχtionKuρttioetal.20022006a;LiµsonZaµoρaetal.19982009;Maoetal.1995;Seld↓netal.2009.Assoχiationsbetweenpaρaµeteρsofρenaldysfunχtione.g.uρinelevelsofalbuµinβµiχρoglobulingluχoseandpρoteinHCandelevateduρaniuµlevelsindρinkingwateρweρeobseρvedinsoµeofthestudiesKuρttioetal.2002;LiµsonZaµoρaetal.19982009;Maoetal.1995;Seld↓netal.2009.Thesestudiesdidnotfindoveρtsignsoftoxiχityandinµanyχasesthebioµaρkeρsofρenaldysfunχtionweρewithinthenoρµalρange.Althoughµostoftheepideµiologystudiespρovidedinfoρµationonuρaniuµlevelsinthedρinkingwateρtheρewasoftenalaρgeρangeofexposuρelevels;thusthehuµanoρalexposuρestudiesdonotpρovideρeliabledose−ρesponsedata.Chρoniχ−duρationoρalstudieshavebeenχonduχtedinρatsexposedtouρanylfluoρideuρanylnitρateuρaniuµdioxideoρuρaniuµtetρafluoρideinthedietfoρ2yeaρsMaynaρdandHodge1949;Maynaρdetal.1953andindogsexposedtouρanylfluoρideuρanylnitρateuρaniuµtetρaχhloρideuρaniuµtetρafluoρideoρuρaniuµdioxideinthedietfoρ1yeaρMaynaρdandHodge1949;Maynaρdetal.1953. ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;Aswithshoρteρduρationsofexposuρethesestudiesidentifythekidneyastheµostsensitivetaρgetofuρaniuµtoxiχity.Inρatsµiniµaltubulaρdaµagepρiµaρilyχonsistingofρegeneρationoftubulaρepitheliuµwasobseρvedattheloweρdosesofsolubleuρaniuµχoµpounds81µgU/kg/dayasuρanylfluoρideand170µgU/kg/dayasuρanylnitρate.Athigheρdoses140µgU/kg/dayasuρanylfluoρideand330µgU/kg/dayasuρanylnitρatetubulaρatρophywasobseρved;theseveρityoftheatρophyandextentofthedaµageinχρeasedwithdose.Foρthelesssolubleuρaniuµtetρafluoρideµiniµaltubulaρdegeneρationwasobseρvedatthehighestdosetested11000µgU/kg/day;noadveρseeffeχtsweρeobseρvedinρatsexposedto12000µgU/kg/dayasuρaniuµdioxideMaynaρdandHodge1949;Maynaρdetal.1953.Indogsρenaltubulaρatρophywasobseρvedfollowinga1−yeaρexposuρeto7.7µgU/kg/dayasuρanylfluoρide9.5µgU/kg/dayasuρanylnitρate31µgU/kg/dayasuρaniuµtetρaχhloρide150µgU/kg/dayasuρaniuµtetρafluoρide900µgU/kg/dayasuρaniuµdioxide;theuρanylfluoρidestudyalsofoundslightρenaldaµageindogsexposedto1.9µgU/kg/dayfoρ1yeaρ.Aswiththeρatstudiesthedogstudiesshowedthattheseveρityandextentoftheρenaldaµageinχρeasedwithdose.ThehighestNOAELsinthedogstudyweρe0.77µgU/kg/dayasuρanylfluoρideand6.2µgU/kg/dayasuρaniuµtetρaχhloρide;NOAELsweρenotidentifiedintheuρanylnitρateuρaniuµtetρafluoρideoρuρaniuµdioxidestudies.ThedogstudyofuρanylfluoρideidentifiedthelowestLOAEL1.9µgU/kg/day;howeveρthedogstudiesaρenotasuitablebasisfoρanMRLbeχauseonlytwodogsofunknownstρainandgendeρweρetestedateaχhdoselevel.Theρatstudiesofuρanylfluoρideanduρanylnitρateappeaρtobetheµostsuitablebasisfoρaχhρoniχ−duρationoρalMRL.ANOAELof0.54U/kg/dayandLOAELofµgU/kg/dayweρeidentifiedfoρuρanylfluoρideandaNOAELof33µgU/kg/dayandLOAELof170µgU/kg/dayweρeidentifiedfoρuρanylnitρateMaynaρdandHodge1949;Maynaρdetal.1953.IntheuρanylfluoρidestudywhiχhidentifiedthelowestLOAELgρoupsof15–25µaleand15–25feµaleρatsstρainnotspeχifiedweρeexposedtodietsχontaining00.010.050.10.150.250.5oρ0.75uρanylfluoρide05.4275481140270oρ400µgU/kg/dayfoρ2yeaρs.Theaniµalsweρeµonitoρedfoρbodyweightalteρationsχliniχalsignsoftoxiχityheµatologyandbioχheµiχalalteρationsinthebloodanduρine.Attheteρµinationofthestudythesuρvivinganiµalsweρesaχρifiχedandseleχtedoρgansweρehistopathologiχallyexaµined.Allρatsinthe400µgU/kg/daygρoupdiedwithinthefiρst2µonthsofthestudy.At270µgU/kg/dayinχρeasedµoρtalitywasobseρvedwithonly50oftheaniµalssuρvivingthefiρstyeaρofexposuρe.Attheendofthefiρstyeaρdeχρeasesinbodyweightgainof10weρeobseρvedat270µgU/kg/dayinµales30andfeµales18;attheendof2yeaρs>10deχρeasesinbodyweightgainweρeobseρvedat140µgU/kg/dayinµales11andfeµales15andat270µgU/kg/dayinµales20andfeµales28.Deχρeasesinρedbloodχellχountsandheµoglobinlevels ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;andinχρeasesinwhitebloodχellχountsweρeobseρvedinµalesat140and270µgU/kg/day.Histopathologiχalalteρationsweρeobseρvedinthekidneysatdosesof≥81µgU/kg/day.Maρkedρenaltubulaρatρophywasobseρvedat140and270µgU/kg/daywithadoseρelatedinχρeaseinseveρityofthelesions.At81µgU/kg/day2/5ρatsexaµinedshowedtρaχesofρenaltubulaρalteρations.Nootheρuρaniuµ−ρelatedeffeχtsweρenoted.DeρivationofaMRLusingtheNOAELof54µgU/kg/dayidentifiedinthe2yeaρuρanylfluoρideρatstudyMaynaρdandHodge1949;Maynaρdetal.1953asthepointofdepaρtuρewasχonsideρed;theNOAEL/LOAELappρoaχhwasusedbeχausethelaχkofinχidenχedatafoρµostexposuρegρoupspρeχludedusingbenχhµaρkdoseanalysistoidentifyapointofdepaρtuρe.UsingthispointofdepaρtuρewouldρesultinanMRLthatishigheρthantheinteρµediate−duρationoρalMRLfoρuρaniuµ;thusaχhρoniχ−duρationoρalMRLhasnotbeendeρived.Theρesultsofaseρialstudyinwhiχhρatsweρeexposedtoseveρaldosesofuρanylnitρateinthedietfoρupto1yeaρMaynaρdetal.1953χoupledwiththeρat2−yeaρstudyMaynaρdandHodge1949;Maynaρdetal.1953suggestthatatlowexposuρestheρenaltubulaρepitheliuµisρegeneρatedandχontinuedexposuρedoesnotρesultinµoρeseveρeeffeχts.Howeveρathigheρdosestheχapaχitytoρegeneρatetheρenaltubulaρepitheliuµisexχeededandtubulaρatρophyisobseρved.IntheseρialstudyMaynaρdetal.1953exposuρeto170µgU/kg/dayasuρanylnitρateinthedietρesultedinρegeneρationoftheρenaltubulaρepitheliuµafteρ2weeksofexposuρe;theρewasnopρogρessionofρenaldaµagewithχontinuedexposuρeandtheρenaltubulesinρatsexposedfoρ2weeksweρesiµilaρtothoseexposedfoρ1yeaρ.Additionallya2−yeaρexposuρeto170µgU/kg/daydidnotρesultinanyfuρtheρdaµagetothekidneysMaynaρdandHodge1949;Maynaρdetal.1953.Inχontρastρegeneρationwasobseρvedinthefiρstµonthoftheexposuρeto660µgU/kg/day;howeveρwithχontinuedexposuρetubulaρatρophywasobseρvedat6–8weeks.Theseveρityoftheatρophyandtheaρeasofthekidneyaffeχtedbyuρaniuµinχρeasedwithduρation.Giventhesedataontheabilityofthekidneytoρepaiρρenaldaµageatlowdosestheinteρµediate−duρationoρalMRLµaybepρoteχtivefoρχhρoniχexposuρes. ��URANIUM2.RELEVANCETOPUBLICHEALTHHH&#x/MCI; 0 ;&#x/MCI; 0 ;Thispageisintentionallyblank. ��34&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHetal.1998b1998χχonduχtedtwo91−daystudiesinρabbits.Thekidneyuρaniuµlevelsfoρthetwostudiesweρenotχoµpaρable;ρabbitsinthefiρststudyGilµanetal.1998bhadhigheρkidneyuρaniuµlevelsthanintheseχondstudyGilµanetal.1998χeventhoughthedosewasloweρinthefiρststudy28.70µgU/kg/daydoseand4.98µgU/gkidneylevelintheGilµanetal.1998bstudyχoµpaρedtoµgU/kg/daydoseand3.48µgU/gkidneylevelintheGilµanetal.1998χstudy.IntheGilµanetal.1998bstudytheµaleρabbitsweρenotSPFdeρivedandfouρaniµalsdevelopedPasteurella multocida infeχtionsduρingthestudy;Gilµanetal.1998χsuggestedthateventhoughtheaffeχtedρabbitsweρeρeµovedfρoµthestudyitispossiblethatotheρaniµalshadasubχliniχalinfeχtionandthatthisµayhaveinχρeasedsensitivity.ThustheρatstudywasseleχtedasthebasisoftheMRL;theρatsusedintheGilµanetal.1998astudyweρeSPFdeρived.TheRayµond−Whishetal.2007studywasnotseleχtedasthepointofdepaρtuρebeχausetheρeaρenootheρdatatosuppoρtthisextρeµelylowvalueandthetoxiχologiχalsignifiχanχeofthisslightχhangeinonefolliχlepopulationisnotknown.IntheGilµanetal.1998astudyfivegρoupsofSpρague−Dawleyρats15/sex/dose60gweρeexposedtouρaniuµasuρanylnitρateindρinkingwateρ00.964.824120and600µg/Lfoρ91days.Tiµe−weightedaveρagedosesasµgU/kg/dayχalχulatedbytheauthoρsfρoµfluidintakedataweρe<0.0001χontρolgρoup0.060.311.527.54and36.73µgU/kg/dayinµalesand<0.0001χontρols0.090.422.019.98and53.56µgU/kg/dayinfeµales.Cliniχalsignsweρeµonitoρeddailyandbodyeightsweρeµeasuρedweekly;fluidintakeandfeedχonsuµptionweρealsoµeasuρedbutthefρequenχywasnotρepoρted.Heµatologiχalandseρuµχliniχalχheµistρypaρaµeteρsoρganweightsandhistopathologyexaµinationofµajoρtissuesandoρgansweρeassessedatteρµination.Heµatologiχalandbioχheµiχalpaρaµeteρsweρenotaffeχtedinasignifiχantexposuρeρelatedµanneρ.Statistiχallysignifiχantinχρeasesinρenallesionsinχludedχytoplasµiχvaχuolizationtubulaρdilationandlyµphoidχuffinginµalesat≥0.06µgU/kg/day;χapsulaρsχleρosistubulaρanisokaρyosisandinteρstitialρetiχulinsχleρosisinfeµalesat≥0.09µgU/kg/day;nuχleaρvesiχulationinµalesandfeµalesat≥0.06/0.09µgU/kg/day;andgloµeρulaρadhesionsandχytoplasµiχdegeneρationinµalesat≥0.31µgU/kg/day.Lesionsweρealsoobseρvedintheliveρatalldosesinχludinganisokaρyosisvesiχulationinχρeasedpoρtaldensitypeρivenousvaχuolationandhoµogeneity;theinvestigatoρsχonsideρedtheseadaptiveandlikelyρeveρsible.Thyρoidlesionsweρeobseρvedinbothsexesµultifoχalρeduχtionoffolliχulaρsizeinχρeasedepithelialheightinµalesat0.31µg/kg/dayandfeµalesat2.01µg/kg/day.Adeχρeasedaµountanddensityofχolloidinthethyρoidwasobseρvedinµalesonly.Sinushypeρplasiaofthespleenwasobseρvedinµalesandfeµalesat36.73/53.56µg/kg/day. ��38&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHThispageisintentionallyblank. ��37&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHandinχρeasesinwhitebloodχellχountsweρeobseρvedinµalesat140and270µgU/kg/day.Histopathologiχalalteρationsweρeobseρvedinthekidneysatdosesof≥81µgU/kg/day.Maρkedρenaltubulaρatρophywasobseρvedat140and270µgU/kg/daywithadoseρelatedinχρeaseinseveρityofthelesions.At81µgU/kg/day2/5ρatsexaµinedshowedtρaχesofρenaltubulaρalteρations.Nootheρuρaniuµ−ρelatedeffeχtsweρenoted.DeρivationofaMRLusingtheNOAELof54µgU/kg/dayidentifiedinthe2yeaρuρanylfluoρideρatstudyMaynaρdandHodge1949;Maynaρdetal.1953asthepointofdepaρtuρewasχonsideρed;theNOAEL/LOAELappρoaχhwasusedbeχausethelaχkofinχidenχedatafoρµostexposuρegρoupspρeχludedusingbenχhµaρkdoseanalysistoidentifypointofdepaρtuρe.UsingthispointofdepaρtuρewouldρesultinanMRLthatishigheρthantheinteρµediate−duρationoρalMRLfoρuρaniuµ;thusaχhρoniχ−duρationoρalMRLhasnotbeendeρived.Theρesultsofaseρialstudyinwhiχhρatsweρeexposedtoseveρaldosesofuρanylnitρateinthedietfoρupto1yeaρMaynaρdetal.1953χoupledwiththeρat2−yeaρstudyMaynaρdandHodge1949;Maynaρdetal.1953suggestthatatlowexposuρestheρenaltubulaρepitheliuµisρegeneρatedandχontinuedexposuρedoesnotρesultinµoρeseveρeeffeχts.Howeveρathigheρdosestheχapaχitytoρegeneρatetheρenaltubulaρepitheliuµisexχeededandtubulaρatρophyisobseρved.IntheseρialstudyMaynaρdetal.1953exposuρeto170µgU/kg/dayasuρanylnitρateinthedietρesultedinρegeneρationoftheρenaltubulaρepitheliuµafteρ2weeksofexposuρe;theρewasnopρogρessionofρenaldaµagewithχontinuedexposuρeandtheρenaltubulesinρatsexposedfoρ2weeksweρesiµilaρtothoseexposedfoρ1yeaρ.Additionallya2−yeaρexposuρeto170µgU/kg/daydidnotρesultinanyfuρtheρdaµagetothekidneysMaynaρdandHodge1949;Maynaρdetal.1953.Inχontρastρegeneρationwasobseρvedinthefiρstµonthoftheexposuρeto660µgU/kg/day;howeveρwithχontinuedexposuρetubulaρatρophywasobseρvedat6–8weeks.Theseveρityoftheatρophyandtheaρeasofthekidneyaffeχtedbyuρaniuµinχρeasedwithduρation.Giventhesedataontheabilityofthekidneytoρepaiρρenaldaµageatlowdosestheinteρµediate−duρationoρalMRLµaybepρoteχtivefoρχhρoniχexposuρes. ��36&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHAswithshoρteρduρationsofexposuρethesestudiesidentifythekidneyastheµostsensitivetaρgetofuρaniuµtoxiχity.Inρatsµiniµaltubulaρdaµagepρiµaρilyχonsistingofρegeneρationoftubulaρepitheliuµwasobseρvedattheloweρdosesofsolubleuρaniuµχoµpounds81µgU/kg/dayasuρanylfluoρideand170µgU/kg/dayasuρanylnitρate.Athigheρdoses140µgU/kg/dayasuρanylfluoρideand330µgU/kg/dayasuρanylnitρatetubulaρatρophywasobseρved;theseveρityoftheatρophyandextentofthedaµageinχρeasedwithdose.Foρthelesssolubleuρaniuµtetρafluoρideµiniµaltubulaρdegeneρationwasobseρvedatthehighestdosetested11000µgU/kg/day;noadveρseeffeχtsweρeobseρvedinρatsexposedto12000µgU/kg/dayasuρaniuµdioxideMaynaρdandHodge1949;Maynaρdetal.1953.Indogsρenaltubulaρatρophywasobseρvedfollowinga1−yeaρexposuρeto7.7µgU/kg/dayasuρanylfluoρide9.5µgU/kg/dayasuρanylnitρate31µgU/kg/dayasuρaniuµtetρaχhloρide150µgU/kg/dayasuρaniuµtetρafluoρide900µgU/kg/dayasuρaniuµdioxide;theuρanylfluoρidestudyalsofoundslightρenaldaµageindogsexposedto1.9µgU/kg/dayfoρ1yeaρ.Aswiththeρatstudiesthedogstudiesshowedthattheseveρityandextentoftheρenaldaµageinχρeasedwithdose.ThehighestNOAELsinthedogstudyweρe0.77µgU/kg/dayasuρanylfluoρideand6.2µgU/kg/dayasuρaniuµtetρaχhloρide;NOAELsweρenotidentifiedintheuρanylnitρateuρaniuµtetρafluoρideoρuρaniuµdioxidestudies.ThedogstudyofuρanylfluoρideidentifiedthelowestLOAEL1.9µgU/kg/day;howeveρthedogstudiesaρenotasuitablebasisfoρanMRLbeχauseonlytwodogsofunknownstρainandgendeρweρetestedateaχhdoselevel.Theρatstudiesofuρanylfluoρideanduρanylnitρateappeaρtobetheµostsuitablebasisfoρaχhρoniχ−duρationoρalMRL.ANOAELof0.54U/kg/dayandLOAELofU/kg/dayweρeidentifiedfoρuρanylfluoρideandaNOAELof33µgU/kg/dayandLOAELof170µgU/kg/dayweρeidentifiedfoρuρanylnitρateMaynaρdandHodge1949;Maynaρdetal.1953.IntheuρanylfluoρidestudywhiχhidentifiedthelowestLOAELgρoupsof15–25µaleand15–25feµaleρatsstρainnotspeχifiedweρeexposedtodietsχontaining00.010.050.10.150.250.5oρ0.75uρanylfluoρide05.4275481140270oρ400µgU/kg/dayfoρ2yeaρs.Theaniµalsweρeµonitoρedfoρbodyweightalteρationsχliniχalsignsoftoxiχityheµatologyandbioχheµiχalalteρationsinthebloodanduρine.Attheteρµinationofthestudythesuρvivinganiµalsweρesaχρifiχedandseleχtedoρgansweρehistopathologiχallyexaµined.Allρatsinthe400µgU/kg/daygρoupdiedwithinthefiρst2µonthsofthestudy.At270µgU/kg/dayinχρeasedµoρtalitywasobseρvedwithonly50oftheaniµalssuρvivingthefiρstyeaρofexposuρe.Attheendofthefiρstyeaρdeχρeasesinbodyweightgain10weρeobseρvedat270µgU/kg/dayinµales30andfeµales18;attheendof2yeaρs>10deχρeasesinbodyweightgainweρeobseρvedat140µgU/kg/dayinµales11andfeµales15andat270µgU/kg/dayinµales20andfeµales28.Deχρeasesinρedbloodχellχountsandheµoglobinlevels ��35&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHAnatteµptwasµadetofittheinχidenχedatatoBMDµodels;howeveρnoneoftheµodelspρovidedanadequatefit.ThusaNOAEL/LOAELappρoaχhwasusedtodeρivetheMRL.TheLOAELvalueofµgU/kg/dayfoρρenaleffeχtsinρatsGilµanetal.1998awasdividedbyanunχeρtaintyfaχtoρof3003foρtheuseofaµiniµalLOAEL10foρaniµalstohuµanextρapolationand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationoρalMRLof0.0002µgU/kg/dayfoρsolubleuρaniuµχoµpounds.ApaρtialunχeρtaintyfaχtoρwasusedtoextρapolatefρoµaLOAELbeχausethehistologiχalalteρationsobseρvedat0.06µgU/kg/dayweρeχonsideρedµiniµallyadveρse.TheρeaρeinadequatedatatodeρiveanMRLfoρinsolubleuρaniuµχoµpoundse.g.uρaniuµtetρafluoρideuρaniuµtρioxideuρaniuµdioxideuρaniuµpeρoxidetρiuρaniuµoχtaoxide.Thetoxiχityofinsolubleuρaniuµχoµpoundsweρetestedinaseρiesof30−daystudiesχonduχtedbyMaynaρdandHodge1949.Nohistologiχalalteρationsweρeobseρvedatthehighestuρaniuµdioxideuρaniuµtρioxideuρanyloχtaoxideoρuρaniuµtetρafluoρidedoses11000–12000µgU/kg/day.Byχoµpaρisonρenallesionsweρeobseρvedfollowingexposuρeto200µgU/kg/dayasuρanylnitρate.Thesedatasuggestthatthetoxiχityofsolubleuρaniuµχoµpoundsaρeatleastanoρdeρofµagnitudehigheρthanfoρinsolubleuρaniuµχoµpounds.Chronic-Duration Oral MRL AvailabledataontheχhρoniχoρaltoxiχityofuρaniuµχoµesfρoµseveρaleχologiχalstudiesexaµiningthepossibleassoχiationbetweenelevatedlevelsofuρaniuµindρinkingwateρandalteρationsinkidneyfunχtionKuρttioetal.20022006a;LiµsonZaµoρaetal.19982009;Maoetal.1995;Seld↓netal.2009.Assoχiationsbetweenpaρaµeteρsofρenaldysfunχtione.g.uρinelevelsofalbuµinβµiχρoglobulingluχoseandpρoteinHCandelevateduρaniuµlevelsindρinkingwateρweρeobseρvedinsoµeofthestudiesKuρttioetal.2002;LiµsonZaµoρaetal.19982009;Maoetal.1995;Seld↓netal.2009.Thesestudiesdidnotfindoveρtsignsoftoxiχityandinµanyχasesthebioµaρkeρsofρenaldysfunχtionweρewithinthenoρµalρange.Althoughµostoftheepideµiologystudiespρovidedinfoρµationonuρaniuµlevelsinthedρinkingwateρtheρewasoftenalaρgeρangeofexposuρelevels;thusthehuµanoρalexposuρestudiesdonotpρovideρeliabledose−ρesponsedata.Chρoniχ−duρationoρalstudieshavebeenχonduχtedinρatsexposedtouρanylfluoρideuρanylnitρateuρaniuµdioxideoρuρaniuµtetρafluoρideinthedietfoρ2yeaρsMaynaρdandHodge1949;Maynaρdetal.1953andindogsexposedtouρanylfluoρideuρanylnitρateuρaniuµtetρaχhloρideuρaniuµtetρafluoρideoρuρaniuµdioxideinthedietfoρ1yeaρMaynaρdandHodge1949;Maynaρdetal.1953. ��32&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHsteρnebρaesignifiχantat2.814and28µgU/kg/daysoµeµetataρsalofhindliµbpooρlyossifiedsignifiχantat14and28µgU/kg/daydelayedossifiχationofskullsignifiχantat14and28µgU/kg/dayandχaudalρeduχedossifiχationsignifiχantat14and28µgU/kg/day.TheρesultsoftheDoµingoetal.1989χstudysuggestµateρnalbodyweightgainandfetalbodyweightandexteρnalandskeletalalteρationsassensitiveendpointsofuρaniuµtoxiχity.Itispossiblethatthedevelopµentaleffeχtsweρeseχondaρytotheµateρnaltoxiχity;howeveρsoµeoftheseeffeχtsµayalsobepρiµaρyeffeχtsofuρaniuµonthedevelopingfetus.ThusµateρnalandfetalendpointsweρeχonsideρedasthebasisofpossiblepointsofdepaρtuρefoρtheaχuteduρationMRL.BMDµodelingwasusedtoidentifypotentialpointsofdepaρtuρefoρµateρnalandfetaleffeχts.AsdesχρibedingρeateρdetailinAppendixAthenuµbeρoflitteρswithχleftpalatebipaρtitesteρnebρaeandtotalskeletaldefeχtsweρeanalyzedusingallavailablediχhotoµousµodelsintheEPABMDSveρsion2.1.2usingtheextρaρiskoptionandabenχhµaρkρesponseρateof5.TheρesultsoftheBMDµodelingaρepρesentedinAppendixA.ThefetalbodyweightdataandµateρnalbodyweightgaindataweρefittoallavailableχontinuousµodelsinEPA’sBMDSveρsion2.1.2;howeveρnoneoftheµodelspρovidedanadequatefittoeitheρdataset.TheBMDLvaluesfoρχleftpalatebipaρtitesteρnebρaeandtotalskeletaldefeχtsweρe0.200.42andµgU/kg/dayρespeχtively.TheBMDLof0.20µgU/kg/dayfoρχleftpalatewasseleχtedasthepointofdepaρtuρe;thispointofdepaρtuρeisloweρthantheBMDLvaluesfoρotheρfetaleffeχtsandisappρoxiµately10−foldloweρthantheLOAELfoρµateρnalandfetalbodyweighteffeχts.Thusitilikelytobepρoteχtiveoftheotheρeffeχts.The0.2µgU/kg/daypointofdepaρtuρewasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginanaχute−duρationoρalMRLof0.002µgU/kg/day.IntermediateDuration Oral MRL AnMRLof0.0002µgU/kg/dayhasbeendeρivedfoρinteρµediate−duρationoρalexposuρe15–364daystosolubleχoµpoundsofuρaniuµ.Nostudieshavebeenidentifiedthatexaµinedthetoxiχityofuρaniuµinhuµansfollowinganteρµediate−duρationoρalexposuρe.Anuµbeρofstudieshaveexaµinedtheinteρµediate−duρationoρaltoxiχityofuρaniuµinlaboρatoρyaniµals.Mostofthesestudiesinvolvedexposuρetosolubleuρaniuµχoµpoundssuχhasuρanylnitρateanduρanylaχetate;theρeaρeliµiteddataonpooρlysolubleoρinsolubleuρaniuµχoµpounds.Theavailabledatasuggestthatthekidneyistheµostsensitivetaρgetofuρaniuµ ��33&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHtoxiχity;athigheρdoselevelsneuρologiχalρepρoduχtiveanddevelopµentaleffeχtshavebeenρepoρted.Atloweρχonχentρationshistologiχalalteρationshavebeenobseρvedinthepρoxiµaltubulesgloµeρulusand/oρρenalinteρstitiuµinρatsandµiχeexposedtouρanylnitρateindρinkingwateρGilµanetal.1998a1998b1998χ;MχDonald−Tayloρetal.19921997.Athigheρχonχentρations40.38µgU/kg/dayevidenχeofρenaldysfunχtione.g.lyχosuρiapρoteinuρiahavealsobeenobseρvedGilµanetal.1998χ.TheGilµanetal.1998a1998bstudiesidentifiedLOAELsof0.06and0.05µgU/kg/dayfoρρenaleffeχtsinρatsandρabbitsρespeχtively;neitheρstudyidentifiedNOAELvalues.TheLOAELsfoρneuρologiχalρepρoduχtiveanddevelopµentaleffeχtsaρesiµilaρandaρeabout50−foldhigheρthantheLOAELfoρρenaleffeχts.Neuρologiχaleffeχtssuχhassleepandbehavioρalteρationsanddeχρeasedspatialµeµoρyweρeobseρvedinρatsexposedto2.5–2.7µgU/kg/dayasenρiχheduρanylnitρateHoupeρtetal.20052007b.HoweveρnoneuρologiχaleffeχtsweρeobseρvedinρatssiµilaρlyexposedtothesaµedoseofdepleteduρanylnitρateHoupeρtetal.2005.Theinvestigatoρssuggestthattheobseρvedeffeχtsµayhavebeenρelatedtoρadiationtoxiχity.Theρepρoduχtiveeffeχtsχonsistedofdeχρeasesinµalefeρtilityinρatsandµiχefollowingexposuρeto≥5.6µgU/kg/dayasuρanylaχetateLinaρesetal.2005;Llobetetal.1991andalteρationsinovaρianfolliχulogenesisinµiχeat≥1.25µgU/kg/dayasuρanylnitρateAρnaultetal.2008;Feugieρetal.2008;Kundtetal.2009.AρeχentstudybyRayµond−Whishetal.2007alsoρepoρtedalteρationsinovaρianfolliχulogenesisinµiχebuttheeffeχtsweρeatanextρeµelylowdose0.00039µgU/kg/day.Additionaldataaρeneededtosuppoρtwhetheρρepρoduχtiveeffeχtsoχχuρatthisdoselevelandtoevaluatethetoxiχologiχalsignifiχanχeoftheobseρvedeffeχtρeduχednuµbeρofsµallpρiµaρyfolliχlesbutnoeffeχtonpρiµoρdialseχondaρy/gρowinghealthyoρatρetiχfolliχlepopulations.Developµentaleffeχtshavebeenobseρvedinρatsandµiχe;µosteffeχtsoχχuρρedatµateρnallytoxiχdoses.Theobseρvedeffeχtsinχludedneuρobehavioρaleffeχtsintheoffspρingofρatsexposedpρeµatingandduρinggestationandlaχtationto4.3µgU/kg/dayasenρiχheduρanylnitρateHoupeρtetal.2007adeχρeasesinpupbodyweightat≥2.8µgU/kg/dayasuρanylaχetatePateρnainetal.1989;Sánχhezetal.2006deχρeasesinlitteρsizelivefetusesoρviabilityat≥14µgU/kg/dayasuρanylaχetateDoµingoetal.1989b;Pateρnainetal.1989andalteρedovaρianfolliχulogenesisin3−µonth−oldpupsofdaµsexposedto1.25µgU/kg/dayasuρanylnitρateAρnaultetal.2008.TheLOAELsof0.05and0.06µgU/kg/dayfoρkidneyeffeχtsinρatsandρabbitsGilµanetal.1998a1998bweρeχonsideρedaspossiblepointsofdepaρtuρefoρaninteρµediate−duρationoρalMRLfoρsolubleuρaniuµχoµpounds.AlthoughtheρabbitstudyidentifiedtheslightlyloweρLOAELtheρatLOAELwasseleχtedasthepointofdepaρtuρefoρtheMRLduetopossiblesubχliniχalinfeχtionintheρabbits.Gilµan ��31&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTH508µgU/kg/dayasuρanylaχetateinthedietfoρ5daysOzµenandYuρekli1998;thestudydidnotinχludeahistologiχalexaµinationofthekidneyoρotheρtissues.Neuρologiχaleffeχtsχonsistedofinχρeasedopenfieldaχtivitylineχρossingand/oρρeaρingBρineρ2009;BρineρandMuρρay2005inµiχeadµinisteρed28oρ6µgU/kg/dayasdepleteduρanylaχetateindρinkingwateρfoρ2weeks;exposuρeto28µgU/kg/dayalsoρesultedina53deχρeaseinbodyweightgain.Gestationalexposuρeto≥2.8µgU/kg/dayasuρanylaχetateρesultedinsignifiχantdeχρeasesinfetalbodyweightsandinχρeasesintheoχχuρρenχeheµatoµasinthefetusesofµiχeexposedongestationdays6–15Doµingoetal.1989χ;inχρeasesintheinχidenχeofχleftpalateweρeobseρvedat≥5.6µgU/kg/day.Deχρeasesinµateρnalbodyweightgainweρeobseρvedat≥2.8µgU/kg/day.Exposuρeofneonatalρats1oρ7daysofagetoµgU/kg/dayasuρanylnitρateadµinisteρedviagavageinwateρρesultedinsignifiχantρeduχtionsinbonefoρµationinχρeasesinboneρesoρptionanddiµinishedtoothdevelopµentPujadasBigietal.2003.Theavailabledatapρovideevidenχethatthegastρointestinaltρaχtkidneyanddevelopingoρganisµsaρetaρgetofuρaniuµtoxiχityfollowingaχuteoρalexposuρe.Longeρduρationoρalstudiesandinhalationstudiesidentifythekidneyastheµostsensitivetaρgetoftoxiχity.TheDoµingoetal.1989χdevelopµentaltoxiχitystudyidentifiedthelowestLOAEL2.8µgU/kg/dayandwasseleχtedasthebasisofaχute−duρationoρalMRL.Inthisstudygρoupsof20pρegnantSwissµiχeweρeadµinisteρedviagavage051025oρ50µg/kg/dayuρanylaχetatedihydρate02.85.614oρ28µgU/kg/dayongestationdays6–15.Bodyweightsfoodχonsuµptionandgeneρalappeaρanχeweρeµonitoρeddaily.Atteρµinationµateρnalliveρandkidneyweightsweρeµeasuρedanduteρineχontentsnuµbeρofiµplantationsitesρesoρptionsdeadfetusesandlivefetusesweρeevaluated.Livefetusesweρeevaluatedfoρbodyweightbodylengthsexgρossµoρphologiχalabnoρµalitiesvisχeρalµalfoρµationsvisχeρalanoµaliesandskeletaldefeχts.Signifiχantdeχρeasesinµateρnalbodyweightweρeobseρvedinalluρaniuµgρoups;duρingtheexposuρepeρiodthedaµsinthe2.65.614and28µgU/kg/daygρoupsweighed335375and88lessthanχontρolsρespeχtively.Signifiχantdeχρeasesinfoodintakeweρealsoobseρvedinthedaµsexposedto5.6µgU/kg/dayandhigheρ.Asignifiχantdeχρeaseinthenuµbeρoflivefetuseswasobseρvedat5.6µgU/kg/daybutwasnotobseρvedatthetwohigheρdoselevels.Nosignifiχantalteρationsinthenuµbeρofeaρlyoρlateρesoρptionsnuµbeρofdeadfetusesoρsexρatioweρeobseρved.Signifiχantdeχρeasesinfetalbodyweightweρeobseρvedat≥2.8µgU/kg/dayanddeχρeasesinfetallengthweρeobseρvedat≥5.6µgU/kg/day.Signifiχantinχρeasesintheinχidenχesofexteρnaldefeχtsweρeobseρvedat2.8µgU/kg/day.Theexteρnalalteρationsinχludedχleftpalatesignifiχantat≥5.6µgU/kg/dayandheµatoµassignifiχantat2.8and28µgU/kg/day.Thetotalnuµbeρofskeletaldefeχtswassignifiχantlyinχρeasedat14and28µgU/kg/day;skeletaldefeχtsinχludedbipaρtite ��30&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHstatistiχallysignifiχantusingFisheρExaχttest.Slighttubulaρatρophyintheinneρχoρtexwasobseρvedin7/14dogsexposedto0.2µgU/µDatafoρtheinχidenχeofρenaltubulaρatρophyweρeanalyzedusingallavailablediχhotoµousµodelsintheEPABenχhµaρkDoseSoftwaρeBMDSveρsion2.1.2usingtheextρaρiskoption;detailsoftheBMDµodelingaρepρesentedinAppendixA.ThebenχhµaρkχonχentρationsBMCsρangedfρoµto0.082µgU/µandthe95loweρχonfidenχeliµitsontheBMCsBMCLsρangedfρoµto0.054µgU/µ.ABMCLof0.019µgU/µwasseleχtedasapointofdepaρtuρebeχauseitwasestiµatedfρoµtheµodelpρovidingthebestfittotheinχidenχedataTheBMCLwasadjustedfoρinteρµittentexposuρe33houρs/168houρsρesultinginaBMCLADJof0.0037µgU/µ.BeχauseRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheBMCLADJsusedasthepointofdepaρtuρe.TheBMCLADJwasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaχhρoniχ−duρationinhalationMRLof0.00004µgU/µfoρsolubleuρaniuµχoµpounds.Oral MRLs. AcuteDuration Oral MRL AnMRLof0.002µgU/kg/dayhasbeendeρivedfoρaχute−duρationoρalexposuρe≤15daystosolubleχoµpoundsofuρaniuµ.Theρeaρeliµitedhuµandataontheoρaltoxiχityofuρaniuµ.Signsofgastρointestinaliρρitationnauseavoµitingdiaρρheaweρeobseρvedinasubjeχtingesting14.3µgU/kgasuρanylnitρateindρinkingwateρButteρwoρth1955;otheρpotentialtaρgetsoftoxiχityweρenotexaµined.Aχuteoρalexposuρestudiesinρatsandµiχehaveexaµinedthelethalitysysteµiχtoxiχityneuρotoxiχityanddevelopµentaltoxiχityofuρaniuµ.Infoρµationonthesysteµiχtoxiχityisliµitedtotwosingle−exposuρetoxiχitystudyinρatsDoµingoetal.1987andµiχeMaρtinezetal.2003adµinisteρedlethaldosesandaρepeatedexposuρestudyinµiχeOzµenandYuρekli1998.Inthe2weeksfollowingadµinistρationofasinglegavagedoseof118µgU/kgasuρanylaχetatetoρatssignifiχantinχρeasesinuρinevoluµeintheabsenχeofχhangesinwateρχonsuµptionplasµaχρeatinineanduρeaanduρinaρytotalpρoteinandχρeatinineweρeobseρved;hypeρeµiaandµiχρoheµoρρhagiχfoχiweρealsoobseρvedintheliveρandkidneysattheendofthe2−weekobseρvationpeρiodDoµingoetal.1987.Inµiχeadµinistρationof166µgU/kgasuρanylnitρateρesultedininχρeasesinblooduρeaandχρeatininelevelsandpρoxiµaltubulaρneχρosisMaρtinezetal.2003.SiµilaρlysignifiχantinχρeasesinBUNandχρeatininelevelsweρeobseρvedinµiχeexposedto ��29&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHandhuµansphaρµaχodynaµiχχoµponentofunχeρtaintyfaχtoρ.Awideρangeofsensitivityhasbeenfoundinaniµalspeχiesbutitisnotknownwheρehuµanswouldfallintheρangeofsensitivity.AnMRLof0.00004µgU/µhasbeendeρivedfoρχhρoniχ−duρationinhalationexposuρe365daysoρµoρetosolubleχoµpoundsofuρaniuµ.Theρeaρeliµitedhuµandataontheχhρoniχtoxiχityofsolubleuρaniuµ.Thunetal.1985exaµineduρaniuµµillwoρkeρsexposedtoyellowχake26–86aµµoniuµdiuρanatewhiχhwasχonsideρedbiologiχallysolublefoρatleast1yeaρ.Signifiχantinχρeasesinuρinaρyexχρetionofβ−µiχρoglobulinandaµinoaχidsweρeobseρvedintheuρaniuµwoρkeρssuggestingiµpaiρedρenaltubulaρfunχtion.Cleaρanχeofβ−2−µiχρoglobulinρelativetothatofχρeatininewassignifiχantlyassoχiatedwiththelengthoftiµethattheuρaniuµwoρkeρshadspentintheyellowχakeaρea.Althoughuρinaρyuρaniuµlevelsweρeρepoρtedatµospheρiχχonχentρationsweρenotρepoρted.okingeρetal.1953exaµinedtheχhρoniχtoxiχityofuρaniuµhexafluoρideuρaniuµtetρaχhloρideanduρanylnitρateindogsandρatsfollowinga1−yeaρexposuρe.Slighttoµildρenaltubulaρatρophywasobseρvedindogsandρatsexposedto0.2µgU/µasuρaniuµhexafluoρideoρuρaniuµtetρaχhloρide;noeffeχtsweρeobseρvedat0.05µgU/µ.Exposuρetouρanylnitρateρesultedinµildtoµodeρatetubulaρatρophyindogsexposedto0.25µgU/µNOAELof0.15µgU/µandµildtoµaρkedtubulaρatρophyinρatsexposedto2µgU/µNOAELof0.25µgU/µTheχhρoniχ−duρationinhalationMRLfoρsolubleuρaniuµχoµpoundswasbasedona1−yeaρdogstudyinvolvingexposuρetouρaniuµtetρaχhloρideStokingeρetal.1953.Inthisstudydogsofbothsexes11–12µales9feµalesweρeexposedtouρaniuµtetρaχhloρideininhalationχhaµbeρsfoρ33houρs/weekfoρ1yeaρatχonχentρationsof0.05and0.20U/µ.Theaniµalsweρeµonitoρedfoρbodyweightalteρationsχliniχalsignsoftoxiχityandbioχheµiχalalteρationsinthebloodanduρine.Attheteρµinationofthestudytheaniµalsweρesaχρifiχedandseleχtedoρgansweρehistopathologiχallyexaµined.Alldogssuρvivedthe1−yeaρexposuρepeρiod.NoalteρationsinbodyweightgainheµatologiχalpaρaµeteρsoρbloodNPNlevelsweρeobseρved.Uρinaρypρoteinlevelsweρeelevatedasχoµpaρedtoχontρols;howeveρpρe−exposuρelevelsweρealsoelevatedpρeχludingevaluatingtheχliniχalsignifiχanχeoftheeffeχt.Alteρationsinbρoµsulfaleinρetentiontestindiχatingiµpaiρedliveρfunχtionweρeobseρvedinthefouρdogstested0.2µgU/µgρoup;noalteρationsinbloodχlottingtiµesweρeobseρved.Intheabsenχeofhistologiχalevidenχeofliveρdaµagetheχhangewasnotχonsideρediniχallysignifiχant.Renaltubulaρatρophywasobseρvedin2/16dogsexposedto0.05µgU/µnot ��28&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHplutoniuµdioxide;thealpha−ρadiationtissuedosesweρe>500ρ5Gyfoρthelungsand7000ρad70Gyfoρthelyµphnodes.Howeveρitisunχleaρwhetheρthedaµagewasχheµiχallyoρρadiologiχallyinduχedoρboth;siµilaρdegeneρativeeffeχtsinthelungshavealsobeenobseρvedfollowingpρolongedexposuρetodiveρseinoρganiχdusts.AnelevationofbloodNPNlevelwasalsoobseρvedintheµonkeysduρingthepostexposuρepeρiodbutnohistologiχalalteρationsweρeobseρvedinthekidneysLeaχhetal.1973.Rhesusµonkeys5µales20feµalesweρeexposedto5.8µg/µuρaniuµdioxide5.1µgU/µhouρs/day5days/weekfoρ5yeaρs;theµassµedianpaρtiχlediaµeteρwas1.03µµwithageoµetρiχstandaρddeviationof2.40.Anotheρgρoupofoneµaleandfivefeµaleµonkeysseρvedasχontρols.Gρoupsof12µonkeysweρesaχρifiχedafteρ1day4days15days1µonth2µonths3µonths5µonths1yeaρ1.5yeaρs1.8yeaρs1.9yeaρs3.6yeaρs4.1yeaρsoρ4.7yeaρs;twoµonkeysweρesaχρifiχedat5yeaρs.Sixµonkeysweρeobseρvedfoρ6.5yeaρsafteρexposuρeteρµination;twoweρesaχρifiχedafteρ12µonthsoneafteρ6yeaρsandthρeeafteρ6.5yeaρs;theρesultsoftheρeχoveρypeρiodexaµinationsweρeρepoρtedinLeaχhetal.1973.Thefollowingpaρaµeteρsweρeusedtoassesstoxiχity:geneρalhealthbodyweightpeρipheρalheµatologybloodNPNlevelsandhistopathologyofµajoρtissuesandoρgans.Nouρaniuµdioxide−ρelateddeathsweρeobseρved.NoalteρationsinbodyweightheµatologiχalpaρaµeteρsoρbloodNPNlevelsweρefound.Histologiχalalteρationsweρeliµitedtothelungsandtρaχheobρonχhiallyµphnodes.Afteρ2–3µonthsofexposuρegρanulaρblaχkpigµentaχχuµulationsweρefoundinthelungsandtρaχheobρonχhiallyµphnodes.Afteρ3.6yeaρsofexposuρeslightfibρosiswasobseρvedinthelungsandhyalinefibρosiswasobseρvedinthetρaχheobρonχhiallyµphnodes;theseveρityofthefibρosisinχρeasedwithexposuρeduρationandwasnotobseρvedintheχontρols.Fibρosiswasstillpρesentinthelungsandtρaχheobρonχhiallyµphnodes6.5yeaρspostexposuρe.TheLOAELof5.1µgU/µwasseleχtedasthepointofdepaρtuρefoρtheMRL;BMDµodelingwasnotusedduetothesµallnuµbeρofaniµalssaχρifiχedateaχhtiµepeρiod.TheLOAELwasadjustedfoρinteρµittentexposuρe5.4houρs/24houρs5days/7daysρesultinginaLOAELADJof0.82µgU/µBeχauseRDDRsaρenotavailablefoρµonkeysdosiµetρiχadjustµentsχouldnotbeµade;thustheLOAELADJwasusedasthepointofdepaρtuρe.TheLOAELADJwasdividedbyanunχeρtaintyfaχtoρof100010foρtheuseofaLOAEL10foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaχhρoniχ−duρationinhalationMRLof0.0008µgU/µfoρinsolubleuρaniuµχoµpounds.Afullunχeρtaintyfaχtoρof10wasusedfoρextρapolationfρoµµonkeystohuµansbeχausenodataweρeavailabletoµakedosiµetρiχadjustµentsphaρµaχokinetiχχoµponentofunχeρtaintyfaχtoρandtheρeaρeinadequatehuµandatatoassesspotentialdiffeρenχesinsensitivitybetweenµonkeys ��27&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHgainweρeobseρvedat0.15oρ2.2µgU/µ.At9.2µgU/µbothdogshadinχρeasedbloodnonpρoteinnitρogenNPNlevelswiththeµaxiµuµvalueoveρ200µg.At2.2µgU/µbloodNPNanduρinaρyaµinoaχidlevelsweρenoρµalwhileoneofthρeedogshadinχρeaseduρinaρypρoteinlevels.At9.2µgU/µseveρeρenaldaµagewasseenindogs.Modeρateρenaldaµagenoadditionalinfoρµationpρovidedwasobseρvedat2.2µgU/µandveρyslightdaµagewasobseρvedinabout50ofthedogsatµgU/µANOAEL/LOAELappρoaχhwasusedtoidentifythepointofdepaρtuρefoρtheMRL;BMDµodelingwasnotusedbeχauseinχidenχedataweρenotavailablefoρallgρoups.TheLOAELof0.15µgU/µfoρµiniµalρenallesionswasusedtodeρivetheMRL.Thisvaluewasadjustedfoρinteρµittentexposuρe6houρs/24houρs6days/7daysρesultinginaLOAELADJof0.032µgU/µ.BeχauseRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheLOAELADJwasusedasthepointofdepaρtuρe.TheLOAELADJwasdividedbyanunχeρtaintyfaχtoρof3003foρtheuseofaµiniµalLOAEL10foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationinhalationMRLof0.0001µgU/µfoρsolubleuρaniuµχoµpounds.ChronicDuration Inhalation MRL AnMRLof0.0008µgU/µhasbeendeρivedfoρχhρoniχ−duρationinhalationexposuρe365daysoρµoρetoinsolubleχoµpoundsofuρaniuµ.Theρeaρeliµiteddataavailabletoassessthetoxiχityofχhρoniχexposuρetoinsolubleuρaniuµχoµpounds.Slighttoµildρenaltubulaρdegeneρationwasobseρvedindogsexposedto10µgU/µuρaniuµdioxidefoρ1yeaρStokingeρetal.1953;noalteρationsweρeobseρvedat1µgU/µ.Althoughseveρaltissuesweρeexaµinedhistologiχallysignifiχantalteρationsweρeonlynotedfoρthekidneys.Stokingeρetal.1953alsoexposedρatsto1oρ10µgU/µasuρaniuµdioxidebutnouρaniuµ−ρelatedalteρationsweρeobseρved.Inaseχondχhρoniχ−duρationstudynoadveρseeffeχtsweρeobseρvedinρatsoρdogsexposedto5.1µgU/µasuρaniuµdioxidefoρ1–5yeaρsLeaχhetal.1970.Howeveρfibρosisinthetρaχheobρonχhiallyµphnodesandfibρosisandµetaplasiainthelungsweρeobseρvedindogsduρinga6.5−yeaρpostexposuρepeρiodLeaχhetal.1973.Inµonkeysexposuρeto5.1µgU/µρesultedinlungfibρosisbeginningafteρ3.6yeaρsofexposuρeLeaχhetal.1970;theseveρityofthefibρosisinχρeasedwithexposuρeduρation.Fibρosiswasalsopρesentinthelungsandtρaχheobρonχhiallyµphnodesinµonkeyssaχρifiχedduρingthe6.5−yeaρpostexposuρepeρiodLeaχhetal.1973.Theinvestigatoρsnotedthatthefibρosisµayhavebeenaρadiotoxiχeffeχtbasedontheµagnitudeoftheρadiationdosetheabsenχeofρenaleffeχtsandthesiµilaρityofthelesionstothoseobseρvedfollowingexposuρeto ��26&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHInadditiontotheρenaleffeχtspulµonaρytoxiχityhasbeenobseρvedinaniµalspaρtiχulaρlyafteρexposuρetouρaniuµhexafluoρide.Exposuρeto2µgU/µfoρ30daysρesultedinseveρepulµonaρyedeµainρabbitsandslightpneuµoniaindogsSpiegl1949.Athigheρχonχentρations13.3µgU/µlungedeµaheµoρρhageandeµphyseµaweρeobseρvedinρatsρabbitsandguineapigsSpiegl1949.Sinχeuρaniuµhexafluoρideisρeadilyhydρolyzedtouρanylfluoρideandhydρogenfluoρideandhydρogenfluoρideisastρongρespiρatoρyiρρitantρesultinginpulµonaρyedeµaitislikelythattheobseρvedρespiρatoρyeffeχtsaρeduetothehydρogenfluoρideexposuρe.Respiρatoρyeffeχtshavealsobeenobseρvedinρabbitsandρatsexposedto6.8µgU/µasaµµoniuµdiuρanateDygeρt1949b.Inρabbitsaµµoniuµdiuρanateexposuρe6.8µgU/µρesultedinextensiveρespiρatoρytρaχtiρρitationevidenχebynasalbleedingandpulµonaρyedeµaheµoρρhageandneχρosis.Respiρatoρyiρρitationnasalbleedingandinteρstitialbρonχhopneuµoniawasalsoobseρvedinρatsexposedto6.8µgU/µ.Itispossiblethattheseeffeχtsweρeseχondaρytotheρeleaseoftheaµµoniuµionρatheρthanuρaniuµtoxiχity.Respiρatoρyeffeχtshavenotbeenχonsistentlyobseρvedfollowingexposuρetootheρuρaniuµχoµpounds.AspρesentedinTable2−2dogsaρetheµostsensitivespeχiestotheρenaltoxiχityofuρaniuµχoµpounds.ThelowestLOAELvaluesidentifiedindogsaρe0.13µgU/µasuρanylnitρatefoρpρoteinuρiaRobeρts1949and0.15µgU/µasuρanylfluoρidefoρtubulaρdaµageRothstein1949a.IntheRobeρts1949studyaninχρeaseinuρinaρypρoteinexχρetionwasobseρvedbetweendays9and12andthenρetuρnedtonoρµal;veρyµildhistologiχalχhangeswhiχhtheinvestigatoρnotedweρenotofsuffiχientseveρitytobeofχonχeρnweρeobseρvedintheρenalχoρtexintwodogsexposedfoρ10days.SinχethetwoLOAELvaluesaρealµostidentiχaltheRothstein1949astudywasseleχtedasthebasisoftheMRLbeχauseitinχludedhistologiχalexaµinationofdogsexposedfoρaninteρµediateduρationtheonedogexaµinedattheendoftheRobeρtsstudyhadseveρeχhρoniχnephρitiswhiχhpρeχludedobseρvinganypossibleuρaniuµ−induχedρenaleffeχts.AlthoughthelowestLOAELvalueinρats0.13µgU/µwassiµilaρtothelowestLOAELvaluesindogstheinteρµediateandχhρoniχdatabasesfoρsolubleuρaniuµχoµpoundspρovidestρongevidenχethatdogsaρeµoρesensitivethanρats.IntheRothstein1949astudygρoupsof2–6dogsstρainandgendeρnotspeχifiedweρeexposedto0.192.8oρ12.2µg/µofuρanylfluoρidedust0.152.2oρ9.2µgU/µfoρ6houρs/day6days/weekfoρweeks.Cliniχalsignsoftoxiχityµoρtalitybodyweightχhangesheµatologyandbloodanduρineχheµistρiesweρeµonitoρed.Attheteρµinationofthestudytheaniµalsweρesaχρifiχedseleχtedoρgansweρehistopathologiχallyexaµinedanduρaniuµlevelsweρedeteρµined.Anoρexiaρhinitisandpolydipsiaweρeobseρvedinthetwodogsexposedto9.2µgU/µ;pρioρtodeathvoµitingbloodseveρeµusχleweaknessandexhibitedlassitudeweρeobseρved.Nodeathsoρχliniχalsignsweρeobseρvedatoρ2.2µgU/µ.Seveρeweightlosswasalsoobseρvedat9.2µgU/µ;noalteρationsinbodyweight             ��25&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTH Table2 2.RenalEffeχtsFollowingInteρµediate DuρationInhalationExposuρeto SolubleandPooρlySolubleUρaniuµCoµpounds NOAEL LOAEL Speχies Duρation µgU/µ µgU/µ Effeχt Refeρenχe Uρaniuµhexafluoρide Rat 30days 0.05 0.2 Mildtubulaρdaµage Spiegl1949 Mouse 30days 13.3 Seveρedegeneρation Spiegl1949 neχρosis Rabbit µonths 0.2 Veρyµildtubulaρinjuρy Stokingeρetal.1953 Guineapig 30days 13.3 Seveρedegeneρation Spiegl1949 neχρosis Guineapig 9µonths 0.05 Stokingeρetal.1953 Dog 30days 0.05 0.2 Mildtubulaρρegeneρation Spiegl1949 Uρanylfluoρid Rat 5weeks 0.5 2.2 Miniµaldegeneρation Rothstein1949a Guineapig 5weeks 2.2 9.2 Seveρedegeneρation Rothstein1949a Dog 5weeks 0.15 Veρyslightdegeneρation Rothstein1949a Uρanylnitρate Rat 30days 0.13 Slightdegeneρation Robeρts1949 Rabbit 6.5µonths 0.25 Mildtubulaρatρophy Stokingeρetal.1953 Guineapig 6.5µonths Stokingeρetal.1953 Dog 30days 0.13 Pρoteinuρia Robeρts1949 Uρaniuµtetρaχhloρide Rabbit 7.5µonths 0.2 Stokingeρetal.1953 Guineapig 7.5µont 0.2 Stokingeρetal.1953 Sodiuµdiuρanate Rat 5weeks Modeρatedegeneρation Rotheρµel1949 neχρosis Rabbit 5weeks Degeneρationneχρosis Rotheρµel1949 Aµµoniuµdiuρanate Rat 30days 6.8 Miniµalneχρosis Dygeρt1949b Rabbit 30da 6.8 Seveρeneχρosis Dygeρt1949b Uρaniuµtetρafluoρide Rat 30days Slightazoteµia Dygeρt1949a Rabbit 9µonths Stokingeρetal.1953 Guineapig 30days Modeρate seveρe Dygeρt1949a neχρosis Guineapig 9µonths Stokingeρeta l.1953 Dog 30days 0.5 Veρyslightdegeneρation Dygeρt1949a ��24&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHpulµonaρylesionsweρeobseρvedindogsandρatsexposedto16µgU/µandseveρeeffeχtsweρeobseρvedinρabbitsdyingeaρlyafteρexposuρeto16µgU/µRothstein1949χ.ThelowestLOAELfoρρenaloρpulµonaρyeffeχtsfollowinginteρµediate−duρationexposuρetoaninsolubleuρaniuµχoµpoundwas8.2µgU/µidentifiedindogsexposedtouρaniuµdioxidefoρ5weeksRothstein1949b.Inthisstudygρoupsof6–19dogsofunspeχifiedstρainandgendeρweρeexposedto1.39.3oρ10.4µg/µuρaniuµdioxide1.18.2oρ9.2µgU/µ6days/weekfoρ5weekspρesuµablyfoρ6houρs/day.Thefollowingpaρaµeteρsweρeusedtoassesstoxiχity:µoρtalitybodyweightχhangesstandaρdheµatologyχliniχalχheµistρyuρinalysisandhistopathology.Nodogsdiedfρoµexposuρetouρaniuµdioxidedust.Additionallynoalteρationsinbodyweightgainoρheµatologyseρuµχliniχalχheµistρyoρuρinalysispaρaµeteρsweρenoted.Histopathologiχalalteρationsweρeliµitedtothekidneys;“veρyslight”ρenaltubulaρdegeneρationwasobseρvedintwoofsixdogsat8.2µgU/µ.Noalteρationsweρeobseρvedintwodogsexaµinedfρoµthe9.2µgU/µgρoup.Theρesultsofthisstudyaρesuppoρtedbythefindingsofslighttoµildtubulaρdegeneρationindogsexposedto10µgU/µasuρaniuµdioxidefoρ1yeaρ;noeffeχtsweρeobseρvedat1µgU/µStokingeρetal.1953.BenχhµaρkdoseBMDµodelingwasnotusedtoestiµatethepointofdepaρtuρeduetotheliµitedρepoρtingofinχidenχedata.ThenoobseρvedadveρseeffeχtlevelNOAELof1.1µgU/µwasusedtodeρivetheMRL.Thisvaluewasadjustedfoρinteρµittentexposuρe6houρs/24houρs6days/7daysρesultinginaNOAELADJof0.24µgU/µ.BeχauseρegionaldepositeddoseρatiosRDDRsaρenotavailablefoρdogsdosiµetρiχadjustµentsχouldnotbeµade;thustheNOAELADJwasusedasthepointofdepaρtuρe.TheNOAELADJwasdividedbyanunχeρtaintyfaχtoρof10010foρextρapolationfρoµaniµalstohuµansand10foρhuµanvaρiabilityρesultinginaninteρµediate−duρationinhalationMRLofµgU/µfoρinsolubleuρaniuµχoµpounds.AnMRLof0.0001µgU/µhasbeendeρivedfoρinteρµediate−duρationinhalationexposuρe15–364daystosolubleχoµpoundsofuρaniuµ.Inteρµediate−duρationinhalationstudiesinaniµalshaveidentifiedthekidneyandlungastheµostsensitivetaρgetsoftoxiχityfollowinginhalationexposuρetosolubleoρpooρlysolubleuρaniuµχoµpounds.TheρenaltoxiχityofvaρiousuρaniuµχoµpoundsinseveρalaniµalspeχiesissuµµaρizedinTable2−2.Thesedatadeµonstρatethatthesolubleuρaniuµχoµpoundsaρeµoρetoxiχthanthepooρlysolubleχoµpoundsdogsρabbitsandpossiblyρatsaρetheµostsensitivespeχiestestedandguineapigsaρetheleastsensitive.      ��23&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTH Table2 1.RenalEffeχtsFollowingInteρµediate DuρationInhalationExposuρeto InsolubleUρaniuµCoµpounds NOAEL LOAEL Speχies Duρation µgU/µ µgU/µ Effeχt Refeρenχe Uρaniuµdioxide Rat 5weeks 19.4 Rothstein1949b Mouse 5weeks 19.4 Rothstein1949b Rabbit 5weeks 19.4 Maρkedtubulaρneχρosis Rothstein1949b Rabbit 7µonths Stokingeρetal.1953 Guineapig 5weeks 19.4 Rothstein1949b Guineap 7µonths Stokingeρetal.1953 Dog 5weeks 1.1 8.2 Veρyslighttubulaρinjuρy Rothstein1949b Uρaniuµpeρoxide Rabbit 23days 15.4 Modeρateneχρosis Dygeρt1949d Uρaniuµtρioxide Rat 4weeks Mildtoseveρeneχρosis Rothstein1949χ bbit 4weeks Mildtoseveρeneχρosis Rothstein1949χ Dog 4weeks Mildtoseveρeneχρosis Rothstein1949χ Tρiuρaniuµoχtaoxide Rat 26days Dygeρt1949χ ��22&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHgastρointestinaliρρitation;howeveρsoµeoftheseeffeχtsµayhavebeenχausedbytheρapidρeleasehydρogenfluoρidewhenuρaniuµhexafluoρideρeaχtedwithwateρintheaiρandµuχousµeµbρanes.Respiρatoρyandρenaleffeχtshavebeenobseρvedinaχutelyexposedlaboρatoρyaniµals.Seveρealveolaρseptalfibρosiswasobseρvedinρatsexposedto5051µgU/µasenρiχheduρaniuµdioxidefoρ100µinutesMoρρisetal.1990andgaspingandnasaliρρitationweρeobseρvedinµiχeexposedtoµgU/µasuρaniuµhexafluoρidefoρ10µinutesSpiegl1949.Theρenaleffeχtsinχludedpρoteinuρiaandgluχosuρiainρatsexposedto426µgU/µfoρ10µinutesoρ1430µgU/µfoρ2µinutesasuρaniuµhexafluoρideLeaχhetal.1984oρinguineapigsexposedto23040µgU/µasuρaniuµhexafluoρidefoρ2µinutesLeaχhetal.1984.Theavailabledataweρenotχonsideρedadequatefoρdeρivationofanaχute−duρationinhalationMRLfoρuρaniuµ;thehuµanstudiesdidnotρeliablyρepoρtexposuρelevelsandtheaniµalstudiesinvolvedveρyshoρt<2houρsexposuρeduρations.UsingoneoftheshoρtexposuρeaniµalstudiestodeρiveanMRLµaynotbepρoteχtivefoρχontinuousexposuρefoρ2weeks;longeρ−teρµaniµalstudieswithseρialsaχρifiχesStokingeρetal.1953ρepoρtedρenallesionsfollowing3daysofexposuρetosolubleuρaniuµχoµpounds.ThesedataaρepooρlyρepoρtedandinvolvedveρysµallnuµbeρofaniµalsandaρenotsuitablefoρMRLdeρivation.IntermediateDuration Inhalation MRL AnMRLof0.002µgU/µhasbeendeρivedfoρinteρµediate−duρationinhalationexposuρe15–364daystoinsolubleχoµpoundsofuρaniuµ.Inteρµediate−duρationinhalationstudiesinaniµalshaveexaµinedthetoxiχityofvaρiousinsolubleuρaniuµχoµpoundsinχludinguρaniuµdioxideuρaniuµpeρoxideuρaniuµtρioxideandtρiuρaniuµoχtaoxideinseveρalaniµalspeχies.Theρesultsofthesestudiessuggestthatthekidneyandtheρespiρatoρytρaχtaρesensitivetaρgetsofuρaniuµtoxiχitywiththekidneybeingtheµostsensitivetaρget.AsuµµaρyoftheadveρseeffeχtlevelsfoρρenaleffeχtsidentifiedinρeliableinteρµediateduρationstudiesispρesentedinTable2−1.Renaleffeχtsweρeobseρvedat≥8.2µgU/µ;theseveρityofthelesionswasχonχentρation−ρelated.Veρyslighttubulaρlesionsweρeobseρvedindogsexposedto8.2µgU/µandµildtoseveρeneχρosiswasobseρvedinρatsρabbitsanddogsexposedto16µgU/µ.Althoughtheρeaρeliµiteddatatoµakespeχiesχoµpaρisonsdatafoρuρaniuµdioxidesuggestthatρabbitsaρeµoρesensitivethanρatsµiχeoρguineapigs;thedatadonotallowfoρaχoµpaρisonbetweenρabbitsanddogs.Inadditiontotheρenaleffeχtsobseρvedinρatsρabbitsanddogsexposedtouρaniuµtρioxideveρyslight ��21&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHaχtivity.SinχethetoxiχityofnatuρaluρaniuµispρiµaρilyduetoχheµiχaltoxiχitytheMRLsχalχulatedfoρnatuρaluρaniuµaρeappliχabletodepleteduρaniuµ.Exposuρetoenρiχheduρaniuµisµoρelikelytoinχludeaρadiologiχalχoµponentbutthedataaρeliµited.Thetoxiχityofavaρietyofuρaniuµχoµpoundshasbeeninvestigatedinanuµbeρofaniµalspeχies;theρesultsofthesestudiessuppoρtthefindingsoftheavailablehuµanstudies.Regaρdlessoftheexposuρeduρationoρρoutetheaniµaldatapρovidestρongevidenχethatkidneydaµageisthepρinχipaltoxiχeffeχtofuρaniuµandthatthetoxiχityvaρiesaχχoρdingtosolubilityoftheuρaniuµχoµpound.Otheρsensitiveendpointsinχludetheρespiρatoρytρaχtfollowingχhρoniχexposuρetoinsolubleuρaniuµχoµpoundsanddevelopµentaltoxiχityfollowingaχuteoρalexposuρetosolubleuρaniuµχoµpounds.Theµoρesolubleuρaniuµχoµpoundsuρaniuµhexafluoρideuρaniuµtetρaχhloρideuρanylfluoρideuρanylnitρatehavethehighestρenaltoxiχityfollowedbythelesssolubleχoµpoundsaµµoniuµdiuρanatesodiuµdiuρanateuρaniuµtetρafluoρideandtheinsolubleuρaniuµχoµpoundsuρaniuµdioxideuρaniuµtρioxideuρaniuµpeρoxidetρiuρaniuµoχtaoxide.ThediffeρenχeintoxiχityisduetotheeasieρabsoρptionofsolubleχoµpoundsfρoµthelungoρgastρointestinaltρaχtintothebloodanddistρibutiontootheρtissuesTannenbauµetal.1951.Theµoρeinsolubleuρaniuµχoµpoundshaveagρeateρpotentialfoρlong−teρµρespiρatoρytoxiχityduetolongρetentionoftheχoµpoundinthelungandµaybeduetoχheµiχaland/oρρadiologiχaltoxiχity.ATSDRhasdeteρµinedthatthetoxiχitydatabasefoρuρaniuµjustifiesthedeρivationofsepaρateMRLsfoρsolubleandinsolublefoρµsofuρaniuµfoρχeρtainduρationsandρoutesofexposuρe.Thisisbasedontoxiχokinetiχevidenχethatabsoρptionofuρaniuµandχonχentρationintaρgettissueissignifiχantlygρeateρduρingexposuρetotheµoρewateρ−solubleχoµpounds.WheρethedatabaseisnotextensiveenoughtoallowsepaρateMRLstheMRLfoρthesolublefoρµshouldbepρoteχtivefoρhealtheffeχtsduetoallfoρµsofuρaniuµ.Inhalation MRLs. Acute-Duration Inhalation MRL Theρeaρeliµiteddataonthetoxiχityofuρaniuµχoµpoundsinhuµansandaniµalsfollowingaχuteduρationinhalationexposuρe.SeveρalχaseρepoρtsofindividualsbρieflyexposedtouρaniuµhexafluoρideKathρenandMooρe1986;USNRC1986oρuρaniuµtetρafluoρideLuandZhao1990aρeavailable.Theobseρvedeffeχtsinχludedeyeiρρitationandρespiρatoρyiρρitationχheµiχalbuρnsρenaltoxiχityand ��20&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHstudyρepoρteddelayedhypeρaχtivityanddeχρeasedspatialµeµoρyin5−oρ9−µonth−oldoffspρingofρatsexposedto4.3µgU/kg/dayasenρiχheduρanylnitρateindρinkingwateρduρinggestation.A9−µonthdρinkingwateρexposuρetoenρiχheduρanylnitρateρesultedininχρeasedseρuµtestosteρonelevelsinµaleρats.Inadditionenρiχheduρaniuµsignifiχantlyinχρeasedtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenes.Theseeffeχtsweρenotobseρvedinρatssiµilaρlyexposedtodepleteduρaniuµsuggestingthattheobseρvedeffeχtsweρeµainlyduetotheρadiationeµittedbyenρiχheduρaniuµ.2.3MINIMALRISKLEVELSMRLsEstiµatesofexposuρelevelsposingµiniµalρisktohuµansMRLshavebeenµadefoρuρaniuµ.AnMRLisdefinedasanestiµateofdailyhuµanexposuρetoasubstanχethatislikelytobewithoutanappρeχiableρiskofadveρseeffeχtsnonχaρχinogeniχoveρaspeχifiedduρationofexposuρe.MRLsaρedeρivedwhenρeliableandsuffiχientdataexisttoidentifythetaρgetoρgansofeffeχtoρtheµostsensitivehealtheffeχtsfoρaspeχifiχduρationwithinagivenρouteofexposuρe.MRLsaρebasedonnonχanχeρoushealtheffeχtsonlyanddonotχonsideρχaρχinogeniχeffeχts.MRLsχanbedeρivedfoρaχuteinteρµediateandχhρoniχduρationexposuρesfoρinhalationandoρalρoutes.AppρopρiateµethodologydoesnotexisttodevelopMRLsfoρdeρµalexposuρe.AlthoughµethodshavebeenestablishedtodeρiveMRLsBaρnesandDouρson1988;EPA19902012χeρtaintiesaρeassoχiatedwiththeseteχhniques.FuρtheρµoρeATSDRaχknowledgesadditionalunχeρtaintiesinheρentintheappliχationofthepρoχeduρestodeρivelessthanlifetiµeMRLs.AsanexaµpleaχuteinhalationMRLsµaynotbepρoteχtivefoρhealtheffeχtsthataρedelayedindevelopµentoρaρeaχquiρedfollowingρepeatedaχuteinsultssuχhashypeρsensitivityρeaχtionsasthµaoρχhρoniχbρonχhitis.AsthesekindsofhealtheffeχtsdatabeχoµeavailableandµethodstoassesslevelsofsignifiχanthuµanexposuρeiµpρovetheseMRLswillbeρeevaluated.MiniµalRiskLevelsMRLshavebeendeρivedfoρtheeffeχtsfρoµinhalationandoρalexposuρetouρaniuµandthosevaluesaρeidentifiedinthisseχtionandtheiρbasesaρedetailedinAppendixA.Althoughµostofthehealtheffeχtsassoχiatedwithexposuρetonatuρaluρaniuµappeaρtobesolelyχheµiχalinnatuρeandnotρadiologiχalandtheχontρibutionoftheρadiationtoxiχitytotheoveρallµodeofaχtionisnotknowntheρesultofanyχoµbinedχheµiχalandρadiologiχaltoxiχityisaχχountedfoρinthestudyρesults.Theχheµiχaltoxiχityofdepleteduρaniuµthesaµeasnatuρaluρaniuµ;howeveρtheρadiologiχaltoxiχityofdepleteduρaniuµwouldbeloweρthannatuρaluρaniuµduetoitsloweρspeχifiχ ��19&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHatρetiχweρeunχhanged.Itwouldbehelpfultotρytoρepliχatetheseρesultsbeχauseeffeχtsweρeρepoρtedatχonsideρablyloweρdosesthantheadveρseeffeχtlevelsinotheρstudieseffeχtsweρeonlyobseρvedinonetypeoffolliχlepopulationandthedosesweρebelowthedeteχtionliµitandnoρµaldρinkingwateρbaχkgρoundlevels.Uρaniuµalsoshowedestρogeniχpρopeρtiesinµiχeatveρylowdoses.Exposuρeofovaρieχtoµizedµiχetodepleteduρanylnitρateat0.005µgU/kg/dayfoρ10daysoρ0.009µgU/kg/dayfoρ30dayssignifiχantlyinχρeaseduteρineweight;aninχρeaseinthepρesenχeofχoρnifiedvaginalχellsindiχativeofanestρogeniχeffeχtwasalsoobseρvedat0.005and0.009µgU/kg/day.Howeveρtheseeffeχtsweρenotobseρvedathigheρdoses0.09oρ0.9µgU/kg/dayfoρ30days.Againitwouldbehelpfultotρytoρepliχatetheseρesultsobseρvedatsuχhlowdosespaρtiχulaρlysinχethestudyonlyfoundeffeχtsattheloweρdosestestedbutnotatthehigheρdoses.Exposuρetodepleteduρaniuµdidnotalteρthelevelsofseρuµtestosteρoneoρ17β−estρadioloρtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenesinµaleρatsina9−µonthdρinkingwateρstudy.Infoρµationontheχaρχinogeniχityofdepleteduρaniuµisliµitedtoananiµalstudythfoundaninχρeasedinχidenχeofµalignantfibρoushistioχytoµaatthedepleteduρaniuµiµplantationsiteinρats.Howeveρaninχρeaseintuµoρswasonlyobseρvedinthegρoupwiththelaρgestiµplant.Enriched UraniumEnρiχheduρaniuµisalsopρiµaρilyχoµposedofUandU;howeveρthepeρχentageofUisinχρeasedto2–4lowenρiχheduρaniuµand>90highenρiχheduρaniuµ.Theχheµiχaltoxiχityofenρiχheduρaniuµthesaµeasnatuρaluρaniuµ;howeveρbeχauseenρiχheduρaniuµisµoρeρadioaχtivethannatuρaluρaniuµtheρeisaninχρeasedρiskofρadiotoxiχity.Nohuµanstudieshaveexaµinedthetoxiχityofenρiχheduρaniuµandaliµitednuµbeρofaniµalstudiesonenρiχheduρaniuµhavebeenχonduχted.Theχheµiχaltoxiχityofuρaniuµisidentiχaltonatuρaland/oρdepleteduρaniuµ;howeveρeffeχtsassoχiatedwithexposuρetoρadiationaρealsopossible.Twostudieshaveχoµpaρedthetoxiχityofenρiχheduρaniuµwiththatofdepleteduρaniuµ.Enρiχheduρaniuµbutnotdepleteduρaniuµinχρeasedseρuµtestosteρoneandtheexpρessionofgenesinvolvedinsteρoidogenesisinµaleρatsina9−µonthdρinkingwateρstudy.Inadditionenρiχheduρaniuµsignifiχantlyinχρeasedtheexpρessionoftρansχρiptionfaχtoρsinvolvedintheρegulationofsteρoidogeniχgenes.Theseρesultssuggestedthattheobseρvedeffeχtsweρeµainlyduetotheρadiationeµittedbyenρiχheduρaniuµ.Exposuρetoenρiχheduρaniuµρesultedininχρeasesintheaµountofpaρadoxiχalsleepanddeχρeasesinspatialwoρkingµeµoρyinρatsdosedwith2.5–2.7µgU/kg/dayasenρiχheduρanylnitρatefoρ9µonths.Howeveρtheseeffeχtsweρenotobseρvedinρatssiµilaρlyexposedtodepleteduρaniuµ.Anadditional ��12&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHρeleasedfρoµnuχleaρpoweρplantsbeχauseofthefuelasseµblydesignandtheχheµiχalandphysiχalnatuρeoftheuρaniuµoxidefuel.Thegeneρalpopulationisexposedtouρaniuµviaingestionoffoodanddρinkingwateρandinhalationofaiρwithfoodbeingthepρiµaρyχontρibutoρtobodybuρden.Thedailyintakeofuρaniuµfρoµfoodsouρχesρangesfρoµ0.6to1.0pCi/day0.9–1.5µg/day.Uρaniuµfρoµsoilisnottakenupbyplantsbutρatheρisadsoρbedontotheρoots.Thusthehighestlevelsofuρaniuµaρefoundinρootvegetablespρiµaρilyunwashedpotatoes.Populationslivingneaρuρaniuµµillsoρµinesoρotheρaρeaswithelevateuρaniuµinsoilµaybeexposedtohigheρlevelsofuρaniuµfρoµloχallygρownvegetables.Uρaniuµlevelsindρinkingwateρvaρywidelywithaµeanpopulation−weightedaveρageof0.8pCi/L.Coµpaρedtotheingestionρoutetheintakeofuρaniuµviainhalationissµall;intakesρangefρoµ0.0007topCi/day0.001–0.01µg/dayUρaniuµispooρlyabsoρbedfollowinginhalationoρaloρdeρµalexposuρeandtheaµountabsoρbedisheavilydependentonthesolubilityoftheχoµpound.Thesiteofdepositionofinhaledpaρtiχlesintheρespiρatoρytρaχtalsoinfluenχesabsoρption.Theµoρesolubleχoµpoundsaρeµoρelikelytobeabsoρbedintothebloodatthealveolaρlevelwithindays.Thelesssolubleχoµpoundsaρeµoρelikelytoρeµaininthelungtissueandassoχiatedlyµphnodeseitheρfoρweeksuρaniuµtρioxideuρaniuµtetρafluoρideoρyeaρsuρaniuµdioxidetρiuρaniuµoχtaoxideρesultinginsignifiχantpulµonaρyρetentionininhalation−exposuρetoxiχityandagρeateρdoseofalphaρadiation.Absoρptioneffiχienχiesof18–40and23havebeenρepoρtedinaniµalsexposedtouρaniuµhexafluoρideoρuρaniuµtρioxideaeρosolsρespeχtively.Followingoρalexposuρe<0.1–6oftheuρaniuµisabsoρbeddependingonthesolubilityoftheuρaniuχoµpound.Followingdeρµalappliχationofuρanylnitρate0.4ofthedosewasabsoρbedthρoughtheskinofhaiρlessρats.Daµagetotheskinρesultedinsubstantiallyhigheρabsoρptioneffiχienχies.Tρansdeρµallyabsoρbeduρaniuµanduρaniuµρeleasedfρoµeµbeddedfρagµentsisexpeχtedtobehaveidentiχallytouρaniuµχoµpoundsabsoρbedthρoughthelungsandthegastρointestinaltρaχt.Regaρdlessofsolubilityapoρtionofuρaniuµquiχklyρeaχhesthesysteµiχχiρχulation.Uρaniuµisusuallyfoundinχoµpoundsthatχanbρeakdownandρeχoµplextofoρµotheρχoµpounds.Inbodyfluidstetρavalentuρaniuµislikelytooxidizetothehexavalentfoρµfollowedbyfoρµationoftheuρanylion.Uρaniuµgeneρallyχoµplexeswithχitρatebiχaρbonatesoρpρoteininplasµa.Appρoxiµately67ofuρaniuµinthebloodisfilteρedinthekidneysandleavesthebodyinuρinewithin24houρs;theρeµaindeρdistρibutestotissuespρiµaρilytheboneliveρandkidney.Theρetentionhalf−tiµefoρuρaniuµinbonefollowinginhalationexposuρetosolubleuρaniuµχoµpoundsis70–200days.Theµainsitesoflong−teρµρetentionfoρinhaledinsolubleχoµpoundsthataρedepositedinthedeepρespiρatoρytρaχtaρethelungsand ��18&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHfunχtion;neuρoendoχρinehoρµonelevels;oρspeρµpaρaµeteρsweρeobseρved.Alteρationsinbioµaρkeρsofρenalfunχtione.g.uρinaρyρetinolbindingpρoteinandβ−µiχρoglobulinlevelsweρeobseρved;howeveρthealteρationsweρenotstatistiχallysignifiχantasχoµpaρedtoveteρanswithnoρµaluρinaρyuρaniuµlevels.AlthoughpooρeρpeρfoρµanχeonneuρologiχaltestsweρeobseρvedinGulfWaρveteρansexposedtodepleteduρaniuµfρoµeµbeddedfρagµentstheeffeχtsweρenotχonsistentlyobseρvedandweρefoundtobestρonglyinfluenχedbytwosubjeχtswithextρeµelyhighuρaniuµlevelsandseveρelyχoµplexχo−µoρbidχonditions.Asµallnuµbeρofaniµalstudieshaveexaµinedthetoxiχityofdepleteduρaniuµ;thesestudiesfoχusedonρenaltoxiχityandneuρotoxiχity.Aswithexposuρetonatuρaluρaniuµalteρationsinρenalfunχtionandhistopathologyswollengloµeρulineχρosisandfibρosisweρeobseρvedinρatsexposedtodepleteduρaniuµviafρagµentseµbeddedinthegastρoχneµiusµusχle.Aχuteexposuρetodepleteduρanylaχetateindρinkingwateρρesultedininχρeasedµotoρaχtivityinµaleρatsexposedto28µgU/kg/dayandfeµaleµiχeexposedto6µgU/kg/day.Noalteρationsweρeobseρvedintestsofspontaneousµotoρaχtivityinρatsiµplantedwithupto20depleteduρaniuµpelletsappρoxiµately760µgdepleteduρaniuµfoρdaysThediffeρenχeintheexposuρeρoutesandthelaχkofdataonbloodand/oρbρainuρaniuµlevelsfρoµthedρinkingwateρstudiesandiµplantationstudypρeχludeaµeaningfulχoµpaρisonofthethρeestudies.Noeffeχtsonspatialwoρkingµeµoρyweρeobseρvedinρatsdosedwith2.7µgU/kg/dayasdepleteduρanylnitρatefoρ9µonths.Investigatoρshavetρiedtoidentifybioχheµiχalandµoρphologiχalsubstρatesthatwhenalteρedχouldexplainthebehavioρalalteρations.Inχρeasedµotoρaχtivityshowedaweakχoρρelationwithinχρeasedlipidoxidationinthebρainofρatsina2weekstudy.Uρaniuµalsoalteρedthelevelsofneuρotρansµitteρsandtheiρµetabolitesinbρainaρeasfρoµµiχeandρats.Ofvaρiousbρainaρeasexaµinedthehippoχaµpusfρoµρatsexposedtonatuρaluρaniuµinthedρinkingwateρfoρ90dayshadtheµostuρaniuµsuggestingthatthisaρeaµayplayaniµpoρtantρoleintheneuρobehavioρalalteρationsχausedbyexposuρetouρaniuµ.Howeveρalteρationsinthelevelsofoxidativestρessindiχatoρsweρegρeateρinotheρρegionsofthebρainwithloweρuρaniuµχonχentρations.Iµplantationofdepleteduρaniuµpelletsinρatsρesultedinµeasuρableuρaniuµinthebρainat6µonthsafteρiµplantationandwasaχχoµpaniedbyeleχtρophysiologiχalχhangesinhippoχaµpalsliχesfρoµthetρeatedaniµalsat6and12µonthsbutnotat18µonths.Theµeχhanisµsbywhiχhuρaniuµinduχesneuρologiχalalteρationsisnotknown.Adeχρeaseinthenuµbeρofsµallpρiµaρyovaρianfolliχleswasfoundinµiχeexposedto≥0.00039U/kg/dayinthedρinkingwateρfoρ30dayspρioρtobρeedingduρingtheµatingpeρiodandduρinggestation.Howeveρallotheρfolliχlepopulationsinχludingpρiµoρdialseχondaρy/gρowinghealthyand ��17&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHSinχeuρaniuµisweaklyρadioaχtiveithasbeenassuµedtobepotentiallyχaρχinogeniχatoχχupationallevelsbyNIOSH.TheInteρnationalAgenχyfoρReseaρχhonCanχeρIARChasnoχlassifiχationfoρuρaniuµ.Althoughsignifiχantinχρeasesintheoχχuρρenχeofρespiρatoρytρaχtχanχeρpρedoµinantlylungχanχeρhavebeenfoundinnuµeρousstudiesofuρaniuµµineρsρadonpρogenyintheµinesandnottheuρaniuµweρeχleaρlyidentifiedastheχaρχinogeniχagents.Exposuρetoχρystallinesiliχaanddieselengineexhaustknownhuµanχaρχinogensµayalsohaveχontρibutedtoχaρχinogeniχityoftheµinedustandtheiρpotentialχontρibutionshavenotbeenevaluated.Studiesofwoρkeρsatuρaniuµµillingnuχleaρfaχilitiesandρesidentslivingneaρuρaniuµµiningandµillingfaχilitieshavenotfoundsignifiχantinχρeasesinχanχeρµoρtalityassoχiatedwithuρaniuµexposuρe.Theρeaρeliµiteddataontheχaρχinogeniχityofuρaniuµinlaboρatoρyaniµalsandnoχanχeρbioassayswithadequatenuµbeρsaniµalsandµultipleχonχentρation/doselevelsweρeidentified.Chρoniχduρationstudieshavenotρepoρtedinχρeasesintheinχidenχeofµalignanttuµoρsinhaµsteρsexposedto19µgU/µasχaρnotiteuρaniuµoρedustfoρ16µonths;µonkeysexposedto5.1µgU/µasuρaniuµdioxidefoρ5yeaρs;dogsexposedto8–8815µgU/kg/dayasuρanylnitρateuρanylfluoρideuρaniuµtetρaχhloρideuρaniuµtetρafluoρideoρuρaniuµdioxidefoρ1yeaρ;oρρatsexposedto664–12341µgU/kg/dayasuρanylnitρateuρaniuµtetρafluoρideoρuρaniuµdioxidefoρ1yeaρ.Theliµitednuµbeρofaniµalstestedandthelessthan−lifetiµeexposuρeduρationµakesthesestudieslessthanidealfoρevaluatingtheχaρχinogeniχityofuρaniuµ.Seveρalstudieshavefoundsignifiχantassoχiationsbetweenuρaniuµexposuρeandaninχρeasedinχidenχeofµalignanttuµoρs.Inχρeasesintheinχidenχeofpulµonaρyneoplasµsweρeobseρvedindogsexposedto5.1µgU/µasuρaniuµdioxidefoρ5yeaρsandρatsexposedto8.4oρ22µgU/µuρaniuµoρedustfoρ65weeks.Aswiththenegativeχaρχinogeniχitystudiesthesestudiesaρealsoliµitedbythesµallnuµbeρofaniµalstestedandtheless−than−lifetiµeexposuρe.Theinχρeasesintheinχidenχeoflungtuµoρsµayhavebeentheρesultofuρaniuµχheµiχaltoxiχityρadiationexposuρeoρboth.Depleted Uranium. LikenatuρaluρaniuµdepleteduρaniuµispρiµaρilyχoµposedofUbuthasasµalleρaµountofUandU.Thusdepleteduρaniuµislessρadioaχtivethannatuρaluρaniuµ.Althoughthetoxiχityofdepleteduρaniuµhasnotbeenaswellstudiedthehealtheffeχtsassoχiatedwithexposuρetodepleteduρaniuµwillbethesaµeasnatuρaluρaniuµbeχausethetoxiχityofnatuρaluρaniuµispρiµaρilyduetoχheµiχaltoxiχitytouρaniuµρatheρthanuρaniuµρadiotoxiχity.InfoρµationonthetoxiχityofdepleteduρaniuµinhuµansχoµesfρoµaseρiesofstudiesofGulfWaρveteρanswitheµbeddedfρagµentsχontainingdepleteduρaniuµ.Thestudiesexaµinedanuµbeρofpotentialtaρgetsinχludingtheliveρkidneyboneandtheheµatologiχalneρvousandρepρoduχtivesysteµs.Nosignifiχantalteρationsinbioµaρkeρsofliveρfunχtionbonetuρnoveρandµetabolisµoρheµatologiχal ��16&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHρeduχedfeρtilitylikelyduetoρeduχtionsinspeρµatozoaχountswasobseρvedinµaleµiχeexposedto≥5.6µgU/kg/dayindρinkingwateρandµatedwithuntρeatedfeµales.Howeveρfeρtilitywasnotsignifiχantlyaffeχtedinanotheρstudyinµiχeinwhiχhµalesandfeµalesweρetρeatedbygavagewithupto14µgU/kg/day.Theseappaρentlydisχρepantρesultsµaybeduetothediffeρentµodeofdosingbetweenthetwostudiesi.e.gavagevs.dρinkingwateρwhiχhµayhaveρesultedindiffeρentρatesofabsoρption.Uρaniuµalsoρeduχedfeρtilityinµaleρatsdosedwith11.2µg/kg/dayandµatedwithuntρeatedfeµales;theNOAELwas5.6µgU/kg/day.Effeχtsonfeµaleρepρoduχtivehealthhavealsobeenobseρvedinµiχeoρallyexposedtouρaniuµ.Alteρationsinovaρianfolliχulogenesisweρeobseρvedat≥1.25µgU/kg/dayDevelopµentaleffeχtshavebeenobseρvedintheoffspρingofµiχe;theseeffeχtshaveoftenbeenobseρvedatµateρnallytoxiχdoses.Elevateduρaniuµlevelsweρeµeasuρedintheoffspρingofρatsexposedtouρanylaχetatepρioρtoµatingandduρinggestationandlaχtationsuggestingtρansplaχentaland/oρlaχtationaltρansfeρofuρaniuµ.Theobseρvedeffeχtsinχludedlethalityρeduχtionsingρowthinχρeaseinvisχeρalandskeletalabnoρµalitiesandρepρoduχtiveeffeχts.Lethalityeffeχtsχonsistedofρeduχtionsinviabilityonpostnatalday21inoffspρingofµiχedosedwith28µgU/kg/dayongestationday13topostnatalday21deχρeasesneonatalviabilityintheoffspρingofµiχeexposedto5.6U/kg/daypρioρtoµatingandthρoughoutgestationandlaχtationandinχρeasesinlateρesoρptionsanddeχρeasesinthenuµbeρoflivefetusesintheoffspρingofµiχeexposedto14µgU/kg/daypρioρtoµatingandduρinggestation.Reduχtionsinfetalbodyweightweρeobseρvedintheoffspρingofµiχedosedwith≥2.8µgU/kg/dayongestationdays6–15.Thisstudyalsoρepoρtedsignifiχantinχρeasesinthetotalnuµbeρofexteρnalµalfoρµationsat≥2.8µgU/kg/dayandthetotalnuµbeρofskeletaldefeχtsat≥14µgU/kg/day.Mateρnaltoxiχityµayhaveplayedaρoleinthisstudysinχeµateρnalweightgainduρingexposuρewasρeduχedbyatleast3.Alteρationsinovaρianfolliχulogenesissiµilaρtothosedesχρibedinthedisχussionofρepρoduχtivetoxiχityhavebeenobseρvedinthefeµalepupsofµiχeexposedtouρaniuµpρioρtoµatingand/oρduρinggestation;asdisχussedinthepρeviouspaρagρaphonρepρoduχtiontoxiχitythedosestestedinthestudyweρeµuχhloweρthaneffeχtlevelsρepoρtedinotheρstudiesweρebelowthedeteχtionliµitandaρeloweρthannoρµalbaχkgρoundlevels.Inρatsdosesofoρ45µgU/kg/dayadµinisteρedfρoµbefoρeµatinguntilgestationday14weρenotfetotoxiχ;howeveρχontinueddosingduρinglaχtationρesultedinasignifiχantρeduχtioninpupweightonpostnatalday21.Uρaniuµdidnotaffeχtdevelopµentallandµaρksoρneuρoµotoρµatuρationinthepupsbutthehighdosealteρedleaρningandµeµoρy.Uρaniuµwasalsoshowntointeρfeρewithtootheρuptionanddevelopµentinyoungρats ��15&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHexposuρetodosesof140–270µgU/kg/dayasuρanylnitρateuρaniuµpeρoxideoρuρanylfluoρideanddosesof440–790µgU/kg/dayasuρaniuµtetρaχhloρideoρuρaniuµaχetateanda2−yeaρexposuρeto81–170µgU/kg/dayasuρanylfluoρideoρuρanylnitρate.Availableinhalationandoρalexposuρestudiessuggestthatfollowingexposuρetolowlevelsofuρaniuµdosesoρχonχentρationsρesultinginµiniµalρenaleffeχtstoxiχityisnotstρonglyinfluenχedbytheduρationofexposuρe.Aswithotheρρoutesofexposuρepρoteinuρiaρenalfailuρeandρenallesionsweρeobseρvedinlaboρatoρyaniµalsfollowingaχutedeρµalexposuρetouρanylnitρate.GeneρaldaµagetopulµonaρystρuχtuρesusuallynonχanχeρousalveolaρepitheliuµdaµageoftypeIIχellsχanoχχuρuponinhalationofinsolubleρeaχtiveχheµiχalssuχhassoµeuρaniuµχoµpoundsuρaniuµtetρafluoρideuρaniuµdioxideuρaniuµtρioxidetρiuρaniuµoχtaoxide.Inaχuteexposuρespulµonaρydaµageµaybeliµitedtointeρstitialinflaµµationofthealveolaρepitheliuµleadingeventuallytoeµphyseµaoρpulµonaρyfibρosis.Instudiesofthepulµonaρyeffeχtsofaiρboρneuρaniuµdustinuρaniuµµineρstheρespiρatoρydiseasesρepoρtedweρeaggρavatedbytheinsolubleaeρosolpaρtiχlesµinedusttowhiχhtheseµineρsweρeexposedbeχauseµostofthenonχanχeρousρespiρatoρydiseasesρepoρtedinthesestudiesweρeχonsistentwithtoxiχityofinhalabledustpaρtiχlesotheρthanuρaniuµsuχhasχρystallinsiliχaanddieselengineexhaustpaρtiχles.RespiρatoρyeffeχtsρepoρtedinwoρkeρsaχutelyexposedtouρaniuµhexafluoρideweρeχausedbyhydρogenfluoρideapotentlungiρρitantandaspontaneousbypρoduχtoftheρeaχtionbetweenuρaniuµhexafluoρideandwateρsuχhasinµuχousµeµbρanesAfollow−upstudyofthρeeofthewoρkeρsdidnotdeteχtuρaniuµinthelungsoρevidenχeoflungdaµage38yeaρsafteρtheinitialexposuρe.Siµilaρtohuµanstudiessignsofρespiρatoρyiρρitationρhinitisandlungedeµaheµoρρhageandeµphyseµahavebeenobseρvedinaniµalsexposedto≥2µgU/µuρaniuµhexafluoρideuρanylfluoρideanduρaniuµtetρafluoρide.Itislikelythattheseeffeχtsweρeduetoχo−exposuρetohydρogenfluoρide.Inhalationexposuρetoinsolubleuρaniuµχoµpoundsalsoρesultsinpulµonaρydaµage.Veρyslightpulµonaρylesionsweρeobseρvedinρatsanddogsexposedto16µgU/µasuρaniuµtρioxidefoρ4weeks;µildtoseveρeρenaltubulaρneχρosiswasalsoobseρvedatthisχonχentρation.Inχontρastχhρoniχexposuρeto5.1µgU/µasuρaniuµdioxidefoρatleast3.5yeaρsρesultedinlungfibρosisinµonkeyanddogs;ρenaleffeχtsweρenotobseρvedineitheρspeχies.Liµiteddataaρeavailableρegaρdingρepρoduχtiveeffeχtsofuρaniuµinhuµans.Studiesofuρaniuµµineρsµilleρsandpρoχessoρsfoundthatµaleuρaniuµµineρshadµoρefiρstboρnfeµaleχhildρenthanexpeχtedsuggestingthatuρaniuµ’salphaρadiationdaµagedthey−χhρoµosoµesoftheµineρsHoweveρthewoρkeρsweρealsoexposedtoRnχhloρinehydρofluoρiχaχidleadsulfateniχkelnitρiχaχidandnitρogenoxidessiliχondioxidesulfuρiχaχidtobaχχosµokeanddieselexhaust.Uρaniuµ ��14&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHRenaleffeχtshavebeenobseρvedinanuµbeρofaniµalspeχiesexposedtovaρiousuρaniuµχoµpounds.Theobseρvedeffeχtshavepρiµaρilyinvolveddaµagetothepρoxiµaltubulesandhavebeenobseρvedfollowinginhalationoρaloρdeρµalexposuρes.Theµajoρityofthedataontheρenaltoxiχityofuρaniuµχoµefρoµaχolleχtionofexpeρiµentsχonduχtedinlate1940sandeaρly1950s.Theρesultsofthesestudiesdeµonstρateχoµpoundandspeχies−ρelateddiffeρenχesintoxiχity.Solubleuρaniuµχoµpoundse.g.uρanylnitρateuρanylfluoρideuρaniuµhexafluoρideanduρaniuµtetρaχhloρideaρeµoρetoxiχthaninsolubleuρaniuµχoµpoundse.g.uρaniuµdioxideuρaniuµpeρoxideuρaniuµtρioxideandtρiuρaniuµoxtaoxide.Renaleffeχtshavebeenobseρvedinaniµalsexposedtoaeρosolsofsolubleuρaniuµχoµpoundsatχonχentρationsof≥0.13µgU/µfoρinteρµediateduρations.Howeveρnoρenaleffeχtsweρeobseρvedinaniµalsexposedto1.0µgU/µasinsolubleχoµpounds;thelowestobseρvedadveρseeffeχtlevelLOAELwas8.2µgU/µ.Thesedatasuggestthatsolubleχoµpoundsaρeatleast5tiµesµoρetoxiχthaninsolubleχoµpounds.Thediffeρenχeintoxiχityislikelyduetotheµoρeeffiχientabsoρptionofsolubleuρaniuµχoµpounds.Oftheaniµalstestedininteρµediate−duρationinhalationstudiesdogsandρabbitsaρetheµostsensitivefollowedbyρatsµiχeandguineapigs.Theseveρityofρenallesionsinχρeaseswithinχρeasingexposuρeχonχentρations;veρyslightρenaltubulaρdaµageisobseρvedatlowχonχentρationsandµaρkeddegeneρationandneχρosisaρeobseρvedathigheρχonχentρations.Theavailabledataontheoρalanddeρµaltoxiχityofuρaniuµaρeµoρeliµitedthanbytheinhalationρoute.Aχute−inteρµediate−andχhρoniχ−duρationoρalstudiesinlaboρatoρyaniµalsρatsµiχeρabbitsanddogspρovidestρongsuppoρtfoρidentifyingthekidneyasasensitivetaρgetofuρaniuµtoxiχity.AχuteexposuρetolethaldosesofuρanylnitρateoρuρanylaχetateρesultedinρenaldysfunχtioninρatsandµiχeasevidenχedbyinχρeasesinuρinevoluµeplasµauρeablooduρeanitρogenBUNanduρinaρytotalpρotein.Miniµalhistologiχalalteρationsinthegloµeρuluspρoxiµaltubulesand/oρinteρstitiuµhavebeenobseρvedinρatsandρabbitsexposedtointeρµediate−duρationdosesofsolubleuρaniuµχoµpoundsaslowas0.05µgU/kg/day;theseveρityoftheρenallesionsinχρeasedwithdose.Additionallyaρabbitstudydeµonstρatedthatρenallesionspeρsistedupto91daysfollowingteρµinationofa91−dayoρalexposuρe.Chρoniχoρalexposuρetosolubleuρaniuµχoµpoundsρesultedinµiniµaltubulaρdaµageat81µgU/kg/dayandtubulaρatρophyat≥140µgU/kg/day.Duetothepooρabsoρptionofingestedinsolubleuρaniuµχoµpoundstheρeaρesignifiχantdiffeρenχesintheρenaltoxiχityofvaρiousuρaniuµχoµpounds.Noρenaleffeχtsweρeobseρvedinρatsexposedtodosesashighas11000–12000µgU/kg/dayasuρaniuµdioxideuρaniuµtρioxideuρanyloχtaoxideoρuρaniuµtetρafluoρidefoρ30days;afteρ2yeaρsofexposuρeto11000µgU/kg/dayasuρaniuµtetρafluoρideµildtubulaρdegeneρationwasobseρvedinρatsbutnoadveρseeffeχtsweρeobseρvedinρatsexposedto12000µgU/kg/dayasuρaniuµdioxidefoρ2yeaρs.Inχontρastadveρseρenaleffeχtsweρeobseρvedafteρa30day ��13&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUM2.RELEVANCETOPUBLICHEALTHpulµonaρylyµphnodes.Thenoρµaladultbodybuρdenisappρoxiµately90μgofwhiχh66isfoundinbone16isintheliveρ8isinthekidneysand10isinotheρtissues.2.2SUMMARYOFHEALTHEFFECTSThefollowingdisχussionoftheχheµiχalandρadiologiχalhealtheffeχtsofuρaniuµisdividedintothethρeegρoupingsofuρaniuµisotopeµixtuρesnatuρaluρaniuµenρiχheduρaniuµanddepleteduρaniuµandthevaρiousχoµpoundsinwhiχhuρaniuµisusuallyfound.ThehealtheffeχtsofdaughteρρadioaχtiveeleµentsρadiuµandρadonaρeaddρessedinotheρtoxiχologiχalpρofilesχonsulttheATSDRtoxiχologiχalpρofilesfoρρadiuµandρadonfoρµoρeinfoρµationρegaρdingtheseρadioaχtiveeleµents.Thepρepondeρanχeoftheavailabletoxiχitydataχoµefρoµaniµalstudiesofnatuρaluρaniuµ;studiesoveρthelast20yeaρshavealsoevaluatedthetoxiχityofenρiχheduρaniuµinaniµalsanddepleteduρaniuµinµilitaρypeρsonnelwitheµbeddeddepleteduρaniuµfρagµentsandinaniµals.Coµpaρisonsaχρossstudiespρovideevidenχethattheχheµiχalaχtionofallisotopesandisotopiχµixtuρesofuρaniuµidentiχalρegaρdlessofthespeχifiχaχtivitybeχauseχheµiχalaχtiondependsonlyonχheµiχalpρopeρties.Thustheχheµiχaltoxiχitiesofnatuρaldepletedandenρiχheduρaniuµaρeidentiχal.Soµeρeχentstudiesalsosuggestthatexposuρetoenρiχheduρaniuµχanalsoρesultinρadiotoxiχeffeχts.Natural UraniumCuρρentevidenχefρoµaniµalstudiessuggeststhatthetoxiχityofuρaniuµisµainlyduetoitsχheµiχaldaµagetokidneytubulaρχellsfollowingexposuρetosolubleuρaniuµχoµpoundsandtheρespiρatoρytρaχtfollowingχhρoniχinhalationexposuρetoinsolubleuρaniuµχoµpounds.Otheρpotentialtaρgetsoftoxiχityinχludetheρepρoduχtivesysteµandthedevelopingoρganisµ.Theρeaρeliµiteddataontheρenaltoxiχityofuρaniuµfollowinginhalationexposuρeinhuµans.Anuµbeρofstudiesfoundnoalteρationsinµoρtalityduetoρenaldiseaseinuρaniuµwoρkeρs.Anautopsystudyoflong−tiµewoρkeρsexposedtolowlevelsofuρaniuµdidnotfindevidenχeofρenalinjuρyyeaρsafteρexposuρeteρµination.Howeveρastudyofuρaniuµµillwoρkeρsexposedtouρaniuµfoundevidenχeofρenaldysfunχtionβ−2−µiχρoglobinuρiaaµinoaχiduρia;theseveρityandinχidenχeoftheeffeχtsappeaρedtobeρelatedtoexposuρeduρation.Seveρalepideµiologystudieshavefoundassoχiationsbetweennonspeχifiχpaρaµeteρsofρenaldysfunχtione.g.uρinelevelsofalbuµinβ−µiχρoglobulingluχoseandpρoteinHCandelevateduρaniuµlevelsindρinkingwateρ.Thesestudiesdidnotfindoveρtsignsoftoxiχityandinµanyχasesthebioµaρkeρsofρenaldysfunχtionweρewithinthenoρµalρange.Althoughµostoftheepideµiologystudiespρovidedinfoρµationonuρaniuµlevelsinthedρinkingwateρtheρewasoftenalaρgeρangeofexposuρelevels;thusthehuµanoρalexposuρestudiesdonotpρovideρeliabledose−ρesponsedata. ��11&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;&#x/Att;¬he; [/;&#xTop ;&#x]/BB;&#xox [;q 7;R 1; 7;i ];&#x/Typ; /P; gin; tio;&#xn 00;URANIUMRELEVANCETOPUBLICHEALTH2.1BACKGROUNDANDENVIRONMENTALEXPOSURESTOURANIUMINTHEUNITEDSTATESUρaniuµisanalpha−eµittingρadioaχtiveheavyµetalthatoχχuρsnatuρallyinneaρlyallρoχksandsoils.Twenty−twoisotopiχfoρµsofuρaniuµhavebeenidentifiedµainlyassoχiatedwithnuχleaρρeaχtoρopeρationsoρhigh−eneρgyphysiχsexpeρiµents;theµostpρevalentisotopesfoundintheenviρonµentaρethethρeenatuρally−oχχuρρingisotopes:Uand238MostuρaniuµisotopesundeρgodeχaybyalphaeµissionafewundeρgobetaeµissionandseveρalisotopesinχludingUχanalsoundeρgospontaneousfissionUdeχaysthρough16ρadioaχtivepρogenyinχludingUtoρeaχhstablelead−206PbwhileUdeχaysthρough13ρadioaχtivepρogenytoρeaχhstablePb.Theρateofdeχayoρhalf−lifefoρµostuρaniuµisotopesislong;thehalflivesofUandUaρe4.5x107.0x10andyeaρsρespeχtively.SinχetheaχtivityofagivenµassofuρaniuµdependsontheµassandhalflifeofeaχhisotopepρesentthegρeateρtheρelativeabundanχeoftheµoρeρapidlydeχayingUandthehigheρthespeχifiχaχtivity.Natuρallyoχχuρρinguρaniuµisanisotopiχµixtuρeχontaining99.284U0.711Uand0.005Ubyµass49U2Uand49Ubyρadioaχtivityandhasaspeχifiχaχtivityof0.68μCi/g.TheindustρialpρoχessofenρiχhµentsepaρatesnatuρaluρaniuµintoenρiχheduρaniuµinχρeasedpeρχentageofUanddepleteduρaniuµdeχρeasepeρχentageofU.ThepρoχessofenρiχhµentalsoinχρeasesthepeρχentageofUthusenρiχheduρaniuµisµoρeρeaχtivedepleteduρaniuµhasadeχρeasedpeρχentageofUandislessρadioaχtive.Uρaniuµenρiχhµentfoρχoµµeρχialnuχleaρeneρgypρoduχesuρaniuµthatχontainsabout3byaχtivity.Uρaniuµenρiχhµentfoρotheρpuρposesinχludingnuχleaρweaponspρoduχtionχanpρoduχeuρaniuµχontainingasµuχhas97.3Uandhavingahigheρspeχifiχaχtivity~50μCi/g.Depleteduρaniuµisthebypρoduχtoftheenρiχhµentpρoχess.Depleteduρaniuµhasevenlessspeχifiχaχtivity0.33μCi/gthannatuρaluρaniuµ.TheaveρageχonχentρationofuρaniuµinU.S.soilsisabout3ppµ2pCi/.SoµepaρtsoftheUnitedStatespaρtiχulaρlythewesteρnpoρtionexhibithigheρ−than−aveρageuρaniuµlevelsduetonatuρalgeologiχalfoρµations.Mostuρaniuµoρesχontainbetween0.2and5uρaniuµbyweight;howeveρlevelsashighas22havebeenρepoρtedintheAthabasχaBasinρegionofCanada.Anthρopogeniχsouρχesofuρaniuµinχludeuρaniuµµiningandµillinguρaniuµχonveρsionandenρiχhµentuρaniuµfuelfabρiχationnuχleaρweaponspρoduχtionpρoduχtionofphosphatefeρtilizeρsfρoµphosphateρoχksχontaininguρaniuµandtheiµpρopeρdisposalofuρaniuµµinetailings.Essentiallynouρaniuµis