Fluoride in Drinking Water A Scientific Review of EPA's Standards (2006) / Chapter Skim
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9 Effects on the Gastrointestinal, Renal, Hepatic, and Immune Systems
9 Effects on the Gastrointestinal, Renal, Hepatic, and Immune Systems
Pages 268-303
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From page 268... ...
gi system Fluoride occurs in drinking water primarily as free fluoride. When ingested some fluorides combine with hydrogen ions to form hydrogen fluoride (HF)
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From page 269... ...
and in a clinical study involving doubleblind tests on subjects drinking water artificially fluoridated at 1.0 mg/L (Grimbergen 1974)
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From page 270... ...
20 ecnerefeR ttobdla W 6591 negrebmirG 4791 grobarteP 7791 namffoH 0891.late .latetgoV 2891 stnemmoC foesodyliad woL foretsulc;ediroufl ehtnodetcelesstcejbus .smotpmysfosisab foesodyliad woL gnitroper-fles;ediroufl .smotpmysfo retsulc;esodyliad woL nodetcelesstcejbusfo .smotpmysfosisabeht retfadevlosersmotpmyS ;detcerrocsaw melborp /gmniedirouflfosesod .detropertonerewgk fostnuomallamsylnO htiwedamsegarevebeht erewretaws'loohcseht .demusnoc /noitacilppA desoporP smsinahce M elbissoP lanitsetniortsag .ytivitisnesrepyh elbissoP lanitsetniortsag .ytivitisnesrepyh elbissoP lanitsetniortsag .ytivitisnesrepyh ediroufletucA foyticixot cirtsageht .muilehtipe ediroufletucA foyticixot cirtsageht .muilehtipe snamuHnistceffElanitsetniortsaGfoseidutS sgnidniF ,niaplanimodba,spmarchcamotS stneitapnehwdevloseraesuandna detadirouflgniknirddeppots .retaw dnahcamotsdahstcejbusfo dah %05 %03;smotpmyslanitsetni .sititamots ,aispidylop,sitirurp,eugitaF lanitsetniortsagdna,sehcadaeh .smotpmys retawnisnoitartnecnocediroulF fo %86.L/gm573dna5.39erew lanitsetniortsagdahnerdlihceht .tespu retawninoitartnecnocediroulF ehtfo %19.L/gm140,1saw .gnitimovdnaaesuandahstcejbus ngiseDydutS fostroperesaC ) 25=n(stneitap yllaicfiitragniknird .retawdetadiroufl tsetdednilb-elbuoD )
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From page 271... ...
21 nesreteP 8891.late rensseG 4991.late namneP 7991.late dnauhdiS remmiK 2002 deunitnoc eudderruccohtaeD ,gnitimov,aesuanot detaeperdna,aehrraid egral(retawfonoitsegni .) esodetuca retfadevlosersmotpmyS ;detcerrocsaw melborp sawedirouflfoesod sawtubdetroperton .gk/gm3ebotdetamitse tonsawgk/gmniesoD .detroper ediroufletucA foyticixot cirtsageht .muilehtipe ediroufletucA foyticixot cirtsageht .muilehtipe ediroufletucA foyticixot cirtsageht .muilehtipe ediroufletucA foyticixot cirtsageht .muilehtipe knardohwsnosrep061ehtfO .sitiretneortsagdah %25;retaw ohwstcejbusfo %2ylnO detroperretawknirdtondid niksdnagnihctI.sitiretneortsag ediroulF.detroperoslahsar tadekaepretawninoitartnecnoc .L/gm15 ,gnitimov,aesuandah %09 ro,sniaplanimodba,aehrraid ecafehtfognilgnitrossenbmun ehtninosrepenO.seitimertxero noitartnecnocediroulF.deidnwot .L/gm051sawretawni etucadahstcejbus43 anissenllilanitsetniortsag .erusopxeretfadoirepruoh-42 retawninoitartnecnocediroulF .L/gm04saw ediroulF.gnitimovdnaaesuaN 29sawretawninoitartnecnoc .L/gm nidetropersmotpmyS gnirudstcejbus123 nideefrevolatnedicca .ylppusretaw detropersmotpmyS afostnediser74ni latnediccagnirudnwot fodeefrevoediroufl .ylppusretaweht detropersmotpmyS fosnortap93ni ohwtnaruatsera roretawdemusnoc deefrevonagnirudeci .tnedicca detropersmotpmyS nerdlihcloohcs7ni latnediccagnirud .deefrevo ongnimussa( L/gm14 L/gm051 hcamotshtiwnoitulid nodesab( )
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From page 272... ...
22 ecnerefeR namtleF lesoKdna 1691 .latekapS 0991 .latesaD 4991 stnemmoC lairtlacinilcfosliateD ,noitazimodnar,.g.e( ton) noitacfiitarts niesod;detroper ;detropertonsawgk/gm smetsyslanitsetniortsag esrowylbaborperew eud(nerdlihcllamsni fo repesodrehgihot ydobfo margolik .)
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From page 273... ...
23 namluhS slle lautca Wdna 7991 sesodetucalatotralimiS noitadirouflretawehtsa .stnediccadeefrevo ehT.eettimmoc gnidnepedyrav 1taediroufl osla htiw diufl eht yb edam hcamotsfo ediroufletucA foyticixot cirtsageht .muilehtipe erewsetamitse Lm 001 htiw 8.0 ylbaborp"aetamitsesrohtuA nerdlihcotedirouflfo"esodcixot ebotegafosraey6nahtssel desabsawesodtahT.gm05 dlihcgk-01afoselpmaxeno ;legFaN %1.1fog1.01gnitsegni g3.33;leg fo FnS 2 %36.0fog7.23 mpp005,1htiwetsaphtootfo htiwetsaphtootfog05;ediroufl Lm122ro;edirouflfo dluocrettalehT.snoitercescirtsagfoetareht dna mpp000,1 .esnirFaN os,denimretedtonsaw %50.0fo hcamots hcamotseht eht ni detulid) detropersawesodsselnu(retaw stroperfonoitaulavE naciremAehtot fonoitaicossA lortnoCnosioP detcepsusfosretneC fonoitsegnirevo etamitseotediroufl fostnuomacixot edirouflesu-emoh edirouflfo niemuloveht .stcudorp noitartnecnoc detadirouflfo Lm ehtgnisu( mpp002 hsawhtuomFaN nognidnepedylediwyrav 004gnitsegni morf %50.0 )
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From page 274... ...
Fluoride supplements are still routinely used today in areas where natural fluoride in the drinking water falls below 0.7 mg/L. In an early clinical trial using fluoride supplements, Feltman and Kosel (1961)
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From page 275... ...
1993) , every fourth person exposed to fluoride in drinking water (<1 to 8 mg/L)
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From page 276... ...
26 ecnerefeR srey na M .late 7991 messA Wdna 2891 onakaN .late 0991 .lateotE 6991 stnemmoC/smsinahce ediroulFfosmsinahce MelbissoP otsawydutsehtfoesopruP decudni-sitilocrehtehwetagitsevni cinolocfonoitcartnocehtnisesaerced ninoitaretlaoteudsielcsumhtooms gnilpuoc-noitcartnoc-noitaticxeeht rotpecerotlatsidetisatassecorp ytilitcartnocniesaerceD.ycnapucco noitazilituderiapmioteudebthgim .muiclacralullecartnifo ssecxeotetubirtnocthgimediroulF lanitsetniortsagninoitcudorpdica .tcart -sissutrepafonoitavitcaelbissoP delpuocnietorp Gevitisnesninixot .msinahcemgnicudsnartlangisaot morftcnitsidebotsraeppanoitcA .ninikotsycelohcybdetavitcataht decudni-YYPecuderthgimFaN tnedneped-nietorp-Gaaivnoitibihni tnednepedni-nietorp-Gadna .yawhtaplanoitcnuf MdnastceffElanitsetniortsaGfoseidutSlaminA sgnidniF decuderyltnacfiingiserewsnoitcartnocdecudni-FaN noslortnochtiwderapmocstarcitiloc cs + ehtdesaerceddna fonoitibihni, Mm5tA. + Mm2ta adesuacedimielamlylodnisibyb .
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From page 277... ...
2 .lateeH 8991 nidraH .late 9991 qiyahS .late 4891 yelhsaP .late 4891 nnamsaE .late 4891 deunitnoc aaivsruccotropsnartediroulF thgimtahtssecorpdetaidem-reirrac htiwedirouflfotropsnartocevlovni HOhtiwedirouflfoegnahcxero + H tropsnartdetceffaediroulF .nolocehtnismsinahcem snoitartnecnocP lanoitapucco MAcfonoitavelE etalumitsnacasocumcirtsagehtni roftnuoccathgimhcihw,tuptuo + H cimednenidetropersmotpmyscirtsag morfrosaerasisoroufl .noitalahniyberusopxe FaNfonoitartnecnocrehgihehT otytilibaemrepcirtsagdesaercni .selucelomegraltontubllams tugehtfoyticixotelbissoP .muilehtipe selcisevenarbmemredrobhsurbybekatpuediroulF ehtniylnotoohsrevonahtiwdnayldiparderrucco .tneidargnotorpdetcerid-drawninafoecneserp yltnacfiingissawnimubla muresenivobfotropsnarT .FaNybdecuder .tuptuodnaytidicacirtsagdesaercnI lacigolotsihtnedneped-emitdna-noitartnecnoC .sllecsuocumecafrusehtotegamad suocumecafrusehtfonoitamauqsed, sllecotegamadlaitnatsbus, Mm01tA Mm05tA.slleclailehtipe raloevofretnidnasgninepodnalgcirtsagehtdnuora .ssolllec nitropsnartediroulF redrobhsurblanitsetni selcisevenarbmem .denimaxe ehtnoFaNfotceffE muresenivobfotropsnart latsidehtssorcanimubla cinoloclamixorpdna M1.0ni(FaN ni(FaN .muilehtipe tarnidecalp) lCH tibbaR tibbaR seidutSoiVnI retawgniknirdnigk/gm52 .syad06rof Mm01ro1 hcamotstarnidecalp)
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From page 278... ...
28 ecnerefeR zsetreK .late 9891 dnaiijuF arumaT 9891 PTN 0991 iluozrahG .late 0002 ihdnoS .late 5991 stnemmoC/smsinahce MelbissoP tceffathgimgninilhcamotsotyrujnI .noiterces ehtfonoigercirolypehtnissendeR eudylekilsienitsetnidnahcamots ,snievllamsehtfonoitaxaleraot fonoitalumuccananignitluser ehtfoasocumehtnidoolbgnitalucric .tcartlanitsetni tugehtfoyticixotedirouflcinorhC .muilehtipe FaNtahttseggussrohtuA asastcadnadicahtiwsetalumucca sanahtrehtar,tnegagnikaerb-reirrab .tnegagnitalumitsnoiterces-sucuma sgnidniF dnanoitamauqsedevisnetxedahstardetaert-FaN emosdewohsslaminadetaert FaC.yrujnillec 2 .ytivitcayrotercesniesaerceddnanoitamauqsed doolbdecuder,hcamotseht morf wofldoolbdecudeR dna,hcamotsehtnislessevdoolbdetalid,muiclac .ssender esuffiD.starelamnihcamotsehtfosnoiselssorG elamefnisisorcenralullechtiwaisalprepyhlasocum .star ;esotcalagdna,esocuf,diuflfotuptuodesaercnI nemulehtfoytidicaelbatartitfonoitcuderdekram naiclAfotnuomadecuderdna;tnedneped Hpsaw -Hpanisucumtnerehdaotdnuobsaweulb .rennamtnednepedni cigolohtapotsiH.desaercedxednicitamosonagrO rebmundesaercnidedulcnienitsetniehtfosegnahc cimsalpotyc,stpyrcdnaillivehtnisllectelbogfo ,sisonkypraelcun,noitaloucavdnanoitalunarged fonoitartlfinicitahpmyldna,sisotimlamronba .airporpanimaldnaasocumbus deunitnoC Mm05dnaFaN retawgniknirdni ni 2-9 ELBAT ydutS Mm001 .yllacirtsagartni FaC 2 taFaNfoesodlaroelgniS .gk/gm003 L/gm003 .shtnom6rof erewstarfoshcamotS Mm02dna5htiwdellitsni .ruoh1rofFaN L/gm001taFaN .syad03rofretawgniknird seicepS taR taR taR taR esuo M
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From page 279... ...
2 aleehsuS saDdna 8891 ihsahS 2002 droftih W .late 7991 llecybdesuacenitsetniehtotyrujnI .gninillasocumehtnihtaed dlohserhtehttahtdedulcnocsrohtuA dnaerutcurtsehtnostcefferof sawasocumcirtsagehtfonoitcnuf .ediroufl Mm1yletamixorppa detaertllanidevresboseitilamronbacigolohpro M illivorcimehtfoecnaraeppa"yalc-dekcarC".slamina lleclailehtipedna muilehtipelanedoudehtfoecafrus .noitareneged ,asocumecafrusehtfohtaedllecdnanoisorE depmulc,dnalgs'rennurBfohtaedllec,egahrromeh siralucsumniselcsumfoyhportrepyhdna,asocumbus tceridnisawreyallasocumfossoL.easocum .erusopxeFaNotnoitroporp ehtnisesaercnidekram,ediroufl negordyhdna,muissatop Mm01dna5tA muidosdnaretawfosexufl ssenderdnagnillewseussitdna,noitercessucum,snoi dekramdewohssmaxecigolohtapotsiH.devresbo foekatpudecuder,reyalllececafrusehtfogninniht dnanoitailofxedezilacol,niatsffihcSdicacidoirep .amededna,sitirtsagetuca,sllececafrusfosisorcen rofegavagybyad/gk/gm01 .sraey2 nevigerewstibbaR fosnoitcejnisuoenatucbus /gk/gm02dna,02,01,5 ehtdna,skeew51rofyad denimaxesaw munedoud .ygolotsihyb htiwasocumhcamotS sawtcatniylppusralucsav ,05,01,5,1otdesopxe niediroufl Mm001dna .stnemirepxetnereffid tibbaR tibbaR goD
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From page 280... ...
(2001) carried out an extensive examination of more than 18,700 people living in India where fluoride concentrations in the drinking water ranged from 3.5 to 4.9 mg/L.
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From page 281... ...
Although it is unlikely that consuming fluoridated drinking water could lead to such high serum fluoride concentrations, one has to consider that subjects who already have impaired kidney function and are unable to excrete fluoride efficiently will retain more fluoride. At this time, there are no studies to distinguish between adverse effects produced by fluoride and the defluorinated metabolites of fluorinated general anesthetics.
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From page 282... ...
Human 18,706 tribal people In endemic areas, fluoride in drinking water was from fluoride endemic 3.5-4.9 mg/L. Prevalence of urolithiasis was 4.6 times and nonendemic areas higher in the endemic area than in the nonendemic of India were evaluated area.
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From page 283... ...
The authors did 1991 not study nephrolithiasis and excessive chronic fluoride intake. Lack of nutrition in the population Water fluoride concentration was at EPA's Singh leads to increases in oxalate current MCLG, but malnutrition among et al.
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From page 284... ...
exposed to fluoride at 2.58 mg/L and in children exposed at 4.51 different concentrations mg/L. Dose-response relationship observed between of fluoride in drinking fluoride concentration and these two measures of water.
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From page 285... ...
GASTROINTESTINAL, RENAL, HEPATIC, AND IMMUNE SYSTEMS 28 Proposed Mechanisms Comments Reference Higuchi et al. 1995 Mitochondrion appears to be Cittanova the target of fluoride toxicity et al.
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From page 286... ...
. Rat 30 and 100 mg/L in Decreased phosphatidylethanolamine and drinking water for 7 phosphatidylcholine phospholipids and ubiquinon months.
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From page 287... ...
GASTROINTESTINAL, RENAL, HEPATIC, AND IMMUNE SYSTEMS 28 Proposed Mechanisms Comments Reference Ca2+ homeostasis appears to Borke have been affected by an increase and in turnover or breakdown Whitford or decreasing the expression 1999 of plasma membrane and endoplasmic reticulum Ca2+-pump proteins. The pathogenesis of chronic Guan fluorosis might be due to oxidative et al.
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From page 288... ...
Evidence of osteodystrophy reported, but did not appear to be of the advanced degree found with skeletal fluorosis. Human Comparison of serum Higher serum fluoride concentrations found in HD fluoride concentrations patients (4.0 ± 0.5 µmol/L)
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From page 289... ...
Suggests bone concentrations alone do not adequately predict skeletal fluorosis. The patients were supplemented with calcium, and were given aluminum hydroxide if serum phosphate was too high.
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From page 290... ...
. Human Serum fluoride Serum fluoride concentrations were approximately concentrations 3.3 times higher in dialysis patients than in healthy measured in 150 subjects.
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From page 291... ...
mineralizing front increases fluoride interacted with aluminum in 2004 mineralization lag time. dialysis patients, altering bone properties.
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From page 292... ...
Patients with Renal Impairment Several investigators have shown that patients with impaired renal function, or on hemodialysis, tend to accumulate fluoride much more quickly than normal. Patients with renal osteodystrophy can have higher fluoride concentrations in their serum (see Table 9-3)
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From page 293... ...
The authors concluded that fluoride-induced alteration in liver membrane lipids could be an important factor in the pathogenesis of chronic fluorosis. Whether any of these changes has relevance to the long-term daily ingestion of drinking water containing fluoride at 4 mg/L will require careful analysis of liver function tests in areas with high and low concentrations of fluoride in the drinking water.
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From page 294... ...
We argue that the concentration of fluoride in these experiments may be within the range `seen' by osteoclasts in mammals treated for prolonged periods with approximately 1 mg of NaF/kg body weight (bw) per day." Sodium fluoride intake at 1 mg/kg/day in humans could result in bone fluoride concentrations that might occur in an elderly person with impaired renal function drinking 2 L of water per day containing fluoride at 4 mg/L (see Chapters 3 and 5 for more information on bone fluoride concentrations)
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From page 295... ...
However, as mentioned previously in this chapter, bone concentrates fluoride and the blood-borne progenitors could be exposed to exceptionally high fluoride concentrations. Thus, more research needs to be carried out before one can state that drinking water containing fluoride at 4 mg/L has no effect on the immune system.
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From page 296... ...
26 FLUORIDE IN DRINKING WATER TABLE 9-4 Effects of Fluoride on Immune System Cells Species Study Findings In itro Human Metabolism factors measured Significant inhibition of PMN metabolic in cultured PMNs incubated activity at 0.1 mM fluoride for O2 generation. with mM concentrations of Activity was also inhibited at 0.5 mM for CO2 14 fluoride.
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From page 297... ...
Effect at 0.5 ppm fluoride likely not Gibson significant. 1992 20 ppm fluoride is 100 times higher than serum fluoride concentrations expected if 1.5 L of 4 ppm fluoride in water is consumed.
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From page 298... ...
Human Blood lymphocytes incubated NaF augmented lymphocyte response to a with NaF at 0.31, 0.62, or mitogen (PHA) or a specific antigen (morbilli 1.2 mM.
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From page 299... ...
GASTROINTESTINAL, RENAL, HEPATIC, AND IMMUNE SYSTEMS 2 Application/Proposed Mechanisms Comments Reference NaF stimulates the early stages of HL-60 Kawase differentiation toward a granulocyte- et al. 1996 like cell.
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From page 300... ...
NaF twice a week for 2-3 weeks and given ovalbumin in drinking water. Rat 0.1, 0.2, and 0.4 mg of Significant PMN-leukocyte infiltration in the fluoride administered lungs observed 24 hours after treatment with intratracheally.
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From page 301... ...
GASTROINTESTINAL, RENAL, HEPATIC, AND IMMUNE SYSTEMS 301 Application/Proposed Mechanisms Comments Reference Antibody formation appears to be General inhibition of metabolic Jain and inhibited because of the decrease function. Susheela in lymphocyte proliferation and 1987 inhibition of protein synthetic ability of immunocytes.
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From page 302... ...
Some effects on liver enzymes have been observed in studies of osteoporosis patients treated with fluoride, but the available data are not sufficient to draw any conclusions about potential risks from low-level long-term exposures. Little data is available on immunologic parameters in human subjects exposed to fluoride from drinking water or osteoporosis therapy, but in vitro and animal data suggest the need for more research in this area.
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From page 303... ...
· It is paramount that careful biochemical studies be conducted to determine what fluoride concentrations occur in the bone and surrounding interstitial fluids from exposure to fluoride in drinking water at up to 4 mg/L, because bone marrow is the source of the progenitors that produce the immune system cells.
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