Document Qgen3237zeGrbqkq47O140aqE

J* * LEAD INDUSTRIES ASSOCIATION uo u e u n o t o n AVCNUI WW YOU* tT, N. T. /UM ?o, 1954 Lwn vrzTtt and i sin KbT iJD" | To ltoabw< of tbo Lm4 J&dootrloo iitocUilocvi *1 oonalderabla Mount of an Inal cxperlaantatloa and a relatively i u U nuabar of clinical til4 have Iodic ated that new drug, calcluu ethyleaedlMlfiatetreaoetate or *CZDT&,t hold* (rt proelae for the treatment of fcuTj motel po ironing, Inc lading lead intoxication** It w* thua that tbo advent of a then quit# new therapy for piuab1m *m announced in bulletin issued by thla offlea on Auguat tit 1952* In tbo inter vening four years, tba promise ha* boon born* out and tbo wledou of mdbering to tbo abbreviation *EXA* of tbo chaolcal nano baa fbund support in avoidance of tbo ooofuaion Incident to tbo aeverel core arc lal naaaoo (hdathasl lt ftillapco, Sequeetreoe, Vereeoe and otbora) by which tbo drug has beeone tooL t. Vo esttsste of the cu^tr of c u m, chlafly of load intoxication, thus far r traatad with ETTA ia poa albls, but that lt la vary fraat la evidenced by the receipt r. of upwarda of a hundred Inqulrlea, stalely from dcaartle aourcae, but also from South Anarlean, European and Auatralaalan countrlea, in thla office alone* Sclantlflc and technical publicatlor.a on EDTA bare alao been Tory numerous, and In following tba developing experience with tba drug, varying ruppllee of law twenty of tbaaa have been acquired. Xneofar aa quantity permlta, thee# may be aw lacted froai a llat ehlcb will be furnished on request, but of only teas have enough for eoeloeure with tbia bulletin. Of the tc reprlnta herewith, that with the title ^Jae of Calc 1m Ethylanediaalnetetraae abate in Caee* of Lead Intoxication* la one of tba aarileat on thla subject, while that on the Vephrotoxlc Hatard free Uncontrolled Edsthaasll - Calelon-Dleodlum Therapy* la one of tba most recant* Aa eaa inevitable with to effective a drug, lta eat aa a preventire of lead Intoxication baa bean advocated In eoae quartere, Condemnation of any Mh propotal at 'dlaeatroua* and *deplor*hle* sea voiced by Dr. R. T. Johnetone in an editorial published In Auguat, lySl4, and aa *rseh and irreeponalbla* and fraught with unknown potential ltlea* in a r,->rt by Dr. *. A. Kahoa in January of tbo following year. Certain of tbaaa advaree potent lal ltlea are nov brought to light la the tecond of our two anoloauraa, in which Sr. Foreman and hit oolleeguaa for tbo firat tine aatabllahed toxic aid# affacta of the drug. *V**rr, mmm, *0 load Ryjlana and ISifrtf Bulletin Mo. 120 -a- Am ?0, 1$$< That carafully controllad traatiMnt of load Intoxication by ooaea of lntraaaooua ETTA la a raluabla Zorn of therapy la d o lon*ar opts to queatloa. ftyalclana having the ear# of ecplayeaa of our oeober ooapanloa who uy dab guid ance to ooatpetant oodlcal aouroaa of InfDnutloo on lta ui ara Invited to oooauoleata d.tb thla offloo. gncloeureai f Manfred BowHteh Wractor of Baalth and Safaty -1 ii P wip --w w --w ijiujiwi^i. im w .iL .j,ia ji^ i i i | ^ * j 11,111 ii.j '.)iiiijfijj.^inj .. n.iujuiiuu .ioii.iii J.JP41 a. , uaait&aOjM*, K*s . B r p' IffntM/ /MM Ik* w 4* N#<* X. /M* rx /M w /M^/M /*. *T 4<ww MiAW iNHtt KtTHROTOXIC HAZARD FROM UNCON. TROLUi) EDATHAM1L CALCIUM-DLSODIUM THIJtAFY nT7 Fit mm, mj x CamHe Fbngaa, Cl Qirort C I MJX, Lm ASmmi, N. Mu, Edachami) cakium-ditodiom. the fikwa chcUte of ctfc)Vacduminrtetr<etic add, a oar dm| tea'll dt*pff>d d m ta he**7 tncui poncoiat.' ba bcce coa- udercd |tarra0y a aoefoak material The foAowiag i> pod pmcuti ckicsl and ctpenmcatel dau indictriag that the compound bat I p*rvotJy oauitpcclcd totic potcotuUrf}. h a hoped chat (ha ac* iataroatioa arfl tem to promote c*vt)od m (be me a# the drag. The etrooeota impmuee d lack of toddty of the drag b bated oa many Mudfea. Toikity attwhet biu beat Made and tho* * that there b a wide tpread htem (he therapeutic dote of 75 mg per kilogram of body atgb aad the L D.to dote. who fro 500 to 7.000 Mg. per kilogram, depending oa the ipedet aad the route of adramntraooa. Metabolic ttmfect doae la thb tahorttory * themed that the eoapoeed b aot wrtah I M. U at (Wn A#m Im AiC >.*> Im*p m r aa I1% I Am rMM A (Vm Nl Mtil m a*--*a a r im h mi a***. a *-i-----a uu t*l*<* ' *. M* (MM. |*ii.*.W \#MM. twm M CM. a 1 AM M (MM*, ft I HUH |>MI mi Mm*. II u* Mm I . M Mmk Mm (WMm Nnm tkMM *--r> * rM * tMi a a a mi mi ni ia h ii m* tmn. t. A. lL M t U. Ml fcM I. (*M >*>*.-- .(A.M*kTwMItAAV., MmI MImI <rnMMMtMl ^l*M fMM| * amt md Tm e Vmm, Cm. ml * DO t mmm h m. a. mu Mml m Mi u i mi i W cm .|..(M..I.iA.| >__I_HI a< m ia I la cw * ( " I (WM i* atm am a,**.m ia it ii > "j^.y. yjwwwjppps* c *! " !.UH.MI.I ^WMMWSJSA^j S.JJAWmf ..V- .3,- N 349.01 Ut*d but iterated rapidly sad virtually completely. (fcu* ppomo| the ctwiriuMOAt of the low loiictty of the dru| Hmnpathological ttudict1 abo support the coo* cHmou ef low toaicity. wet DO pathofcficaJ changer Mi the ttttur* appeared after large dote* W jiw*. Rwanty, homr, there have been arvtral c*w It wtuch M bi appeared chat the drug tt not m Imo o mw a* 0w show atudie* indicated. Dudley and other** recently reported two cate*. both from the Masascho* cm Ocoetil HotptUi, tmpMcatmf cdathamil at * lotk agent. A 50-year-old woman and a 4Vi -year-old child, both of whom had terminal catc*. were grwn (he od*tm Mb of (h< drug hi anempta to lower eJrrated tcrom calcium levels Autopiy eiammation revealed evert damage of the rcwal tubule* and widespread e* ftxgenKM of the rrticukcodotbehaJ cefl*. with coane touoophdic grtowiet and tileaihe internal hemorrhage, all of which the author* felt coaid beat be tiffined a* the result of the rdtfhamfl therapy. Foflowtng k a report of a cat* (hat occurred at U Alamos. lUpaet of a Cota tiatminbia juiawiwiMinwiwiailO >w ptd m*k krauto wtaoii wtoMJ >Miwitnl > --si M4y twrOr* f pliiiia* mrwmmlf omt MH later*t* 4otol awwtoi a Wv t x mw to (to towS. awf M a Mn d m** to (MHMMto |Uwn * Two iti Mtf |nm of toHhwl mki-- Qiirtoii to 290 to tow wetmuom Ht 11*11110 Nw toh H MtfiHWM 4np an Ulftoo rwi Tto lew toiiarti fwto wae for 4 itfi W w Mlcsto ty 3 4*9* to rr*. to tto iwH yv( (M toog >i* iwni lor IS wntmr 4m h t* laoito dw nfWtoiiity M to >0% to toe tod* totri to ftoama nwii ty to* 4ntoto . Oa toe II* . to* yotooa \ ftoo to owocto Mo*, towtor. 1 too tot pw Tto l*n*w<*a 4*1 toe ) *0*1^1 tone mmo tod Mi to* fimtt cwtofMiMd to e4toi to tor too** are word ttoifto to awtrwto Mi fnto*acy. wyaty. and M a. Hart*. a. C, I.I WW a. me Data, to to! OM *--Mil M U 4 WM ItoWi POMH luiOM f Willi Ill IMI MW to 9 (Ml VM 1 h m iiiiui-tn iiMki ion i. *M I to a k a M* Wa lettow (Mi toe "WfaW!i|pfp^ o i- f,. 4* a*irto*f m artowioa TW*rr uli the dm# *pfw4 tto* ni imMiaviiwo to it* canto to Mr in**-- w* admtoew. hryweto etMdiMtKto aawwtnMnory. hkud neeptto* Of> t*4 cbeooOry, Wktlvdt** ooprurrM aNroye* lr*t %*** wtthMi aorpMl V**w tor a* *kw4 erom cakivrs Into to 11 *to f** (00 oc. IWm, Wwnvr. 4mi 2+ dtoh muwcrcM mot c*iiv a**y ftor frsetoar (M*v a*4 w w b mI rvd ui whito bW>4 c*JH The wm ti n*nurn* to de fttol MidoMr Aitpf r-to rapidly aftor 4to 0*1 two to tr*oiM*oi hr Oto Mdi 4r ft* wru* ** (War *a4 tM foiieor appeared rweWr mn*r#d from iM coone to rtoan. D amand (Mi Oae iMwuuw* to tM dr*e * ftootod t* (Mae* of the inripKttd anocirtioa of renal dan* ape wtoh cdathaai) therapy m the three case* described above, a wa* decided to rttne*t*cst* (he (oaktoy of Che dnrf to determine if renal patholopcml cha|c* coaid be prodoccd eipcnmcnUHy with edathamd In tabora* lory anarruh ft teemed to be particularly important to drlertotoc the denafe trvei required to prodoct the dam* aft in relation to the amount of (he drug (hat would haw to be med for thetapeviic eftcctmoeiA Male Sprapue-Dawicy rat*. wri^hio| appro*imtody 400 pa. each, were nto in all of the tfwhea. The hrto of the ttfenneaa waa carried out with twpralcthal dewafe leveh. in order to be a* certain a poaubk of the production of IrtoooA To yroup* of ait tats each were ftw J,ooo mg per kOopraa and 1.000 np per hflo* fram per dy re*fectrwe^. The aoimaH wrv kyected itorapemoemlty c**cr dally with a toiulip* conuminf 10% edathamd cilciuto dnoilnicn aod 1% procaine (Novocato). which was added to control the discomfort of the injection. Control antmah were inJaded with pro* caine akme k order to rale out the possibility of fhn agent kfluenctof the letiona. Urine wa* coOecied and a* anwned lor durifea k voUame, pH. peci6c gravity, afbumto. and aedaoent. Afl antmah hvkf after daft of kjectioot were Lilkd Tissue* were taken a* toon as poatoNr after death and iaed promptly by immersion r>- - 1 i-;' pg' 4 la a formaldehyde CFomalinJand mercuric chloride rota tion Sections were prtfwred and turned by (be standard brmaioiyfja-eoua method. After It was dcmooitraled that kidney lesion* did develop, further studies wtie earned out at lower donga levcb The medtaa effective dotaye levH (t Dm), that k. the amount of tl-c drug required to product the first hhtolotxal evidence of damage in 50% of the sntmals treated daily for !6 days, w at determined Four group* of five rate each were injected intrepentoorally dadjr with 5% edathami) caroum-dnodrum at dotage level* of 62 5. 125, 250, and 500 mg. per kilogram Titaue* foe hntopathological ttudy were taken at fat the prrvioua experiments Another group of rata war treated with 500 mg per kilogram per day for 16 dayt and then abroad to recover foe 50 dayt before taaiUcr, fat order to lean whether recovery wat cm a hittological at well at a dadcal bate*. A Kith group of rata was injected with odathamd atroeitMim-dtaodruffl at a dotage level of 250 mg. per kilogram per day for 16 days to iod whether tha strontium form of the compound products lesions. Aa addition*! eapenmc*: was earned owl fat order la de termine the effect of pH of the urme oa the drvetop nent of the kidney lc*Am* One group of tit rats was gtvea 0.25% ammonium chlordc m the dat and an other group 0 25% at sodium bicarbonate ia the diet. Edathami) calcruro-dimdnim, 3,000 and 1.000 mg. per kilogram, was wacd tat this eaperiment- Aa aatrnpt waa made to determine the pathogenesis of the tonal Into* and to look foe lesions la other organa. Two group* of 12 rau each were given 500 and 1.000 mg per kilogram of the drag daily httrapemoaeaHy. Two rata la each group were then killed by a blow oa the head 6. 12 24, 41, and 96 boon after the bit in jection. They were then ecamincd aa quickly aa pouibk. and p*ecca of the heart bver, and kidney were from la isopentane at -50 C and Chen dehydrated and embedded la parafba under vacuum. Other basnet hud ia formal dehyde cad mercuric chloride mtatare of hcmefoiylm i s i f r. : ir i r1 v and eo-ttaifled paraffin sections were: thyroid, para thyroid, bean, liver, ipken, kidney, adrenal gland, amah ioteKinc, and colon Kidney and total body weight! were obtained at Out tunc The from and dehydrated ftttuet were studied foe cytotogicn! changrt in the ptoaimal con voluted tubule*, foe change* la glycogen content with Betti carmine Main, and for fat '..Kh oil red O. The Hudm ahowed that the drug could cautc a toaic nephroan cumtaimg of aevetx hydropic degeneratioo of the proermal tubule* (ate figure). None of the other tntuea dimmed thowed pathological changes. AS cf die ammalt rtcenmg doaaget of I gm. per kilogram or higher developed kidney know U they received daily injection! for a tafhoent length of tame. The animals that received 3.000 mg. per kilogram per day developed kaioos ra 41 hours; tboic dut received 1.000 mg per kilogram per day showed the first ugn* of kidney dam age after four day* of injection The tnuinh receiving dosages of 125. 250, and 500 mg per kilogram per day developed lesions at tome time between 4 and 16 days of treatment, but tome of these dad not develop Icaiom ; at all Noee of the annuls developed kiom with a daily dote of 625 mg per kilogram given foe (he 16 days. It it of interest that rat* have been given 40 in jection* of 100 mg pee kilogram per day without evi dence of renal damage.* The EOuki ammah treated daily for 16 days, a* calculated by Thompaoo'i moving atefige technique.' w 2tll mg per kilogram. with a 95% probability of the effective dote falling in the rmyt -t between 1)1 and 314 mg pee kilogram. Annuli that were treated with 500 mg pee kilogram per day far 16 i days and then killed 30 days after injection* warn stopped showed complete bmotogaca! recovery. The group treated with edathamtl itrootium-daodium do- 4 Tta****. V | Va 4 tfH6rt iM t^tyniaM Malx f*a* | hiteagMM '--ifte A IsHMIM * tsrm. Mi Ota tantata tat ta. Ill Ota# t veloped the name ledon at the animate treated with edalhtmll calcrum-diwdrum Animate recetviog procaine akm ikMtd d o Udat) kuna Dan were d o Mn* encet between th* witter) fiodmgt of (be mated animate aad of die controla la pH. volume, and albumin coolent. but unoe of (he treated tmmsh showed mawy cattl aad epithelial edit. la aahnak recTtvmg 5.000 ag per llopaa, al oa a normal dal or with aaunowwm chloride la their dret died wirhra three to alt da)t Three owl of la of the lodarai bicarbonate (rowp aurvived the (ad sU daft, bwt they vert terminally moribund at thb time AS of (be aafanah receiving the kmer doujo aurvtvrd the fall experiment and acre killed at that time. At the time of death all of die animals had lorn betaera 10 aad 15** of their Martial weight. la the ealmsh treated with the lower donee, (he path ological chanfes were limited to the proximal eoavolatad Uibulrx. With treatment of 350 m| per kilogram, occauoaal loop* of the tubule adjacent to a glomerulus thowed nuclear pyknoaw aad huge lotracyioptaunic vacuolex with deMractioo of cell weDa. Further along the proximal coavdsled tubule the cytoplasm waa dis torted b) mnuaarrabtc MBaBcr aad irregularly tired vacuolex, which gave a a tew-lAe appearance, re thoww la the figure. A. There the anda were nor ehcred The ether tabulet appeared normal With the 500 mg. pee kilogram dote of the drag, thrt levert hydropic degen eration wwt lowed to have eatewded to about had of each proximal convoluted tubule The rrat of the tubular ijatem thowed hne droplet degenrradon, at thoww la the figure. I. la the ran that needed 1,000 ag of edathamd per Upgraea. aiatoM the cwtire proximal cow- gone kjdrapc degeneration. with the loematieo of baft uacwolee and la tome lantern raptare of cel walla, aa thown in the figure, C. Ocxnwontlh. a foewt of obetruf the aephrota tcea ataoewted with apparrm oedutioa of a coOceting Iwbwle with debate. la Ike rare receiving the higher dote (J.OnOmg pet kilogram), the; atom revere changes were tern. The hydropic ftpettete^ k ' boo of the proximal coevoluted tubwlct wat fwty frJreBt' vetoprd. aad la many arena free Spare. Pi only the basement memtenaea rewvanrd. aha, there waa wo aiga of the peccahtmg octU oe (heir component para, la addmoa. there waa parentbywisVowv drgencfstxw el At dwtal coovolwied twbulev Hit change appeared aa nweleae pylwout and chroatatofyaie aad graawlar nmoephom iatratabwlnr debtin. la Hcnle'e loops. aderea of oceaatonal cefle owe area, canting the loranetoa of to*  ik Wla.ftBwiTrfcffc''- .nilftll--inri r called bird-rye cxlh. la addition. (beet were hyaline and amorphous cacii la the collecting uibotcv, and above these area) o( obtlrvctioa tblalatxm ofth mote proxi mal portions of the iuhuiev wav area, la tome instance! (he glomerular tufti appeared edematous, and there wal protetnovd ptectpoait w the glomerular capMile. la lie aectxau from the rata killed a^urstuD) dor* la| the adrairuiireuei of 5fiQ and 1.000 mg per kilo gram of the drug. the renal Iruoa wet aeea to develop at the end of four ftp with the Urger 4~ve No leikm aere rero la the other organs examined The special ataia* foe gtycogea la the frorea and dehydrated Imam failed lo chow the accumulation of Out substance la either the kidney oe heart or the Io m of it from the hepatic parenchyma. Staim loe fat were umilaefy noncontributory. The hcmatotylia-covin-vtained sections of the quickly frorea kidneys, however, ihowtd that the hyaline droplcti of the cytoplasm of the proximat con* vohited tubule* Bxreared gnralfy la tire wrth tune nti the vacuoles developed Theac dropirta teemed to be hrghly waver-voluble, unce the ordinary method at hatoInpxal debydratjoa appeared to remove them. Waving the vieve-bke appearance at the renal cytoplasm. The tafiihtt appearance of kidney lessons following repealed adnumsusticw of odathamd calcwn-dii idea at high doirv dcfauvely cvtaMavbev the nephrotoxic po tenttailry of the drug and supports the opouon that the renal tkiiqei drvcrvhed In the cavcv above revolted front dathamk admmwiratioa Repealed doaet are ncccvaary before levicmt can be demonstrated hmMy a Hath date could produce lesions. but dm dm* nould have to be vo high that u would be lethal. The revufcs vhour that there It an interTtUttonvhrp between the tire of the dore and the length of time required to produce the kidney damage. It n reavonable to expect that, because of the revtruble nature of the lesion. there it a threshold dove--the dove below which Irviona never develop no nutter how tong the drug k administered Thh threshold f. kt Vjr- 'i 9 would be the amount of the drug from which the rate of recovery would be greater than the rat* of production of Injury TV.a came eflecl would obtain with higher* than-Threshold" dovev by allowing longer period) of time loe recovery Imervpcrvjtg red period! brio any prolonged treatment regimen would, therefore. Mem very advisable The lad that repeated dovev are necea- vaiy loe development of levaoea might explain the tack at hhicpathotopcal lesions in the ttodrea reported.' Probably edathamil waa not given tar a long enough tuna to pew-act the renal lextona. The data obtained from our experiment! with rats afford an tadxenoa of dovev that might be expected to produce leuoru la man and aho provide a comparing wrth therapeutic dovage tovck On the baaet of the EDsa tor rats treated dafly foe 16 dayv U might be expected that 501 of patients weighing 150 lb. (6k kg.), who received M gm a day for 16 dayv. would develop kidney ,f lesions. Leva than 2 51 of then* given 9 gm. of the drug under the tame condaiont would develop no- ' I phrotk, while only 23% of individual) given 22 gm. j would be cipocted to cveape such damage, fa order that development cf tosioos occur In 4 days. 70 gm. would have to be given daily to a 150-lb man. although tuck ! ,j j a person could be pvea 4.5 gm. daily for at kaet Id L dayv without ddhcuhy The recommeodcd therapeutic I dovage level of 5 gm a day. given not mart than it* dayv m vucccwloo and followed by a two-day rest pg> j nod.' would aeon to be writ withia Ik* desirable safety i Inatta. ' la the fatal cavcv repotted by Dwficy aaf othcrv* dm adult patent who weighed 122 ftt. (33.) kg ) received : 5 to 6 gm. cm two rueccwrve dayv followed by tug dayv* rest. and then II to 22 gm. (330 to 440 mg. pae j kilogram) toe ame successive dayv On the bnue of tba j data given above, that individual had a high probability r Haw o value caaa Nawanww mem a tfvaMm H*n Htmt NdWMa ftMM* M ft**# M WM (mm M AHA. A* Mm HiViM (M.) Mi 1 10 of developrng renal It wont in a similar manner. it might have been predicted that the other patient had only a fair probability of develi,pirig a nephrotu from treat ment with 1 gm for three ilryi fnOowtd by J gm. (200 mg per kilogram! for (S days la the Los Alsraoa caw the low dose, equivalent to 7 gm. duty for a J M'fb man, would not have hrra ctpcctcd to came trouble In more than 2 % of tha even to treated fa the experiment re ported her* < cooId not hod any lyncrgntic /acton, such at urinary pH. that coukl captain this unexpected enhancement it n possible, though, that loch (acton at general status <4 health. endocrine balance, renal dracare, and - or abnormal renal function could enhance the nephrotoxic action Both the calcium chcliie and the sodium aah of edathamd cauie kidney damage. The sedaua lone of the compound convert! to the calcium chelate on con tact with mum ealemm. and. hence, the ndmlnistratiou of other the cektum or todiutn dern stive tewha hi the calcvum chelate aa the form passing through the ksdney. Dudley and othera ' pentulated that, when the wine pH fait* to 5 oe below, there k a dtvsociabon of the ealemm chelate, wtth rrleaae of fit* calcium are in the tnaue fluid of the kadney, which could being about the lopay. Data from the experiment! reported here do not aupfaxt thu hypothesis. If the lowering of the pH a the tubular flwidi Iradt to a chain of otati that rtauh la kidney Injury, darn, the noimala that rroctve lodiutn bicarbonate In thru diet mould have been eaperted la vhow mber no kidney Irsions or at lead leaver injury than the animals rocctvtng emmofunm chloride in theft rhrt. There eu no difference histologically, hmtttf, between the damaged kidneys of the two group* of antmak. Morcoecr. the atroniMmi chelate produced kidney damage. The deleteriout reaction noted above ia more bkely brought about through the chelation propenict of the compound, and k b prohabfy the until portion of an administered dote, noted at metabohun atudiea to tare Over very slowly. that It Involved. The drug could very t0 bind with a trace metal occctaary foe the function , r 11 of an caaentiat cstryme system. Since this aw* be metai forming a chelate n>;h a higher stability coaatant than the cekium chciale, magnesium la unlikely 10 he involved Iron, and perhapt manganese. art more hkety roetsl mm The interruption of a metalmlic chain by in activation of as caaestial tniymatic function could ex plain Du development of nephrosis A break In the metabolic pathuay could cautc metahoiitet to accumu late. which would increase the eytopUimle osmotic prrauire. leading to hnNbrtua of iter by (he cell and the type of hydropic degeneration that occurred in the rati The location of (he Icuon in (be proximal convoluted tybulet and the gisdacot of decreasing damage In the diatal portiooa of the renal tubule would teem to impli cate a metabolite curetcd by (he gioencnih and mbcurbed by the proximal convoluted tubule. The huto chemical ttudiex made here fail to give a bruit to (hit hypothecs oe to show an accumulation of glycogen and closely related sugars. Further Itudicx. however, of (ho mode of action of edathamd in producing (hit nepbroala ate in peogrexa The renal Icuon In the rat la remarkably sundae to that ocoxrnag in man.* The eormophilic amorphout debnt in (he reticular macrophagta of the tuwo found at autopty of the two patienta waa not found, however, in the rata. The demonstration of the hazard of ratal damage oc curring with the therapeutic me of edathaoif thouid Ml be eonudeted at a came for Mopping cluneal we of the drug. Edathamd hax proved too useful chaicaDy to at trition any curtailment in Us me. The fcvers*sly of the lesions and the prolonged administration of targe dotet of the drug tequetd to produce lexiona offer obnoos meant of using rdithamil safely. At aa ad ditional tafety (actor, it is recommended that the drug he med in doses approsimatmg SO mg. per kilogram pet day. given loe fcve days, followed by two days of real Its me should always be attended by daily oriaafysle and should he stopped al once with (he onset of ligna of renal tubular alteration. Whether the existence of various stages of acute and chronic nephritis preclude* use of the drug is not known, but logically k would scent Pg1,1 y] > i'W.m.W v/r IIA10932 : > 5 l'. F' 12 necessary to fwocced with esirrme caution ia the pres ence of t nephritis. Toxic nephrosis. such u mercurial poisoning. would certain!) teem to cidude the ux cl edalhamd because of the danger of synergistic enhance ment of the ncphiotic damage with ordinary safe dotage level* ot the drug The occurrence of toxic nephrosis is a woman under therapy with edathamfl caicrum-dtsodnun lor mobdixa- tioe ol plutonium prompted cspcrsmrntal mavesttgition of the toxicity and hittopatholop ot the drug Numerous experiment* done oo rats demonstrated for the tint time that edathamil h a potentially haxardoux drag, since, on repealed administration of moderately large doses, k produced nephrosis Tha speciftc nature of the lesion was severe hydropic degeneration of the proximal tubules. The lesion was found to be reversible and was cleared withm a lew days after crasation of admusistrw- tion of the drug. None of the other tissues of the body that were examined appeared to be afleeted. The E. D (amount of the drag respond to produce the im hnto- logical evsdeace of damage tat JOW ot (he anicniH treated daily (or 16 days) was 20) mg. pee kilogram at body weight per day. With a dose of 62.5 mg. pee kilo gram pet day , no kidney tesiom were demonstrated. The results of these experiments should peomose caution in use of (he drug. The reversibility of the lesiona 5 and the prolonged adminHtralioa ol Urge doves of the drug inquired to produce kvorss oflee an obvious means for using the dreg safely. It is suggested that the drug be .1 i used In doses of approximately 30 mg pee kilogram per day. given foe tit days, and followed by two days of J. rest before the regimen is repeated. Daily urmalysi* should be done during the treatment period, and, svitkl onset of unusual urinary (ladings, adraituiustioa of the drug should be stopped The presence of acute or chronic a renal disease should probably cause reluctance In me of the drug. T. O In IM) (Of. fertwwx i M Jtifi kJsrf }rr>m W A. V. A Arfkm^i Imdm***/ 1/ *W CVnyM*<f M*rfw*W i*U Kef f. ff. 144 W C+tyr**k*. /?JJ. Fj V*rf*W ^M>fnhi im of c a l c iu m rrHnfNfoiAMmrrmuucrrATi tw CAiES Of UAt> INTOXICATION '- 1 1 K KAtMAH, MJL W *1, WCT> H MR, K L NA19T, lit T. L VWN4AH. MJl l L IGDUf, MJL IS RESPONSE to tat contaderabl* hrtrte* which by been rupmid U cal cium ethyWncduumnrtrtraaceUtr (Ca EDTA),* * new drug iurb *how promt** ta the treatment of heavy-metal pennaewog. we art iu{{oti^ a protocol lot the u*e at i) drug ia Wad iotoxkstioa. The pirpoftc of tuggeking a uniform mode oi treating pnbeot* with thU drug k to prumete the oac at caae material at efficiently at poarnMc ia gathering informaboo abcot the drug It it hofed that during the** mkial *Uge* the trial ot the drug win be fanned to exjenrtxed chnical investigator* with adequate Udlitjca lor ohcfVttkn and follow-up of the patient*. A* an aid to well Mimtipton, wt hare aommanjed (he experience in the ate of the drug m human* to date and are iadiati^ a dotage achedwW baaed 00 toxicity atodwa in ammaU. Theae atodirt were carried oot by Dr. George Mabofl of the Department of FTtanmcotofy, Boaton Dahrenitjr School of Medicine.* Mr. Manfred Bowditch, Director of Health and Safety of the Lead ladsitrin Aaaociation. haa agreed to hold a regittry of ouch protocol* of am of tew) poieooinf treated with Ca EDTA in hb office at 420 Leamgtm Ave, Kew York 17. It U planned by tbi^ meant to make the information coQected cmtraDy mikbk for atidy. L (s) ******* S. r . Rd M, wd Wmbi* M: Ud Ma Dk Citmmti* )**. mi (I) Sitary. J. A.: firwwl twwwiiratinw % If. tdn (*) Mkw*a 7. L: IdwL Med ttiXd, mZ (4) Van Ordnraad H. &: Peru--I CMHMarttr* la tW aufKara <r) rtwnW, F. Pnc. Sac. F.*r**. Bid A Med W:ltt, mi. if) Unk 0. ad kMki At Perwaial newnf4tetwei to M Bdd <*) CnAw* aad Sk(1w> bkith: Btrmal com* --katw ta M Rabtot (*) Onut, W. U firirwl iwamraine to M. Bdd (0 Gfkn R F. aad RiraxM. 5 - ). Ural- ItSI. </) Aba dawn. R, and WiMw* T.i J. Urxd MtU*. 1*51. (*) Kma. A, and Katriw*. S *eWnr* tti W. *5d <I> FotoavH A.; CnrtoHiW. C F ; AeWnkjr. A. t*4 Bdk M.: Fr $*. Kt*c. Bk A Med TlirflS, IWO. () rofrrrVL A.; Gewtorlief. C. F. and JtaMa. M 7* be fOrfidwd () CewWrklee, C f ' FFert erf Qvteting fraftariui l A*4k Cakl--S fw#4 Mwt Rwtifi| erf BifrVkiril rrcffM Dinrton, Nr Ywi Feh Jtk, mi. Z Ca KOTA m*j be dowH by wrtoa-g A*Wr tjWetvek l. NO IWt c v V Bhi, Lei Angeha. .-wuengn 1 i^aa.*i^pi5itonn,..|i .i.yMiijitui I N 349.02 2 AM* raarocot rot t h i im or C* EPTA im u l a o h t t o x ic a t io x 1. T# MmI Ov *Ac<7 O EfTA k artrUrurt^ th* rifrrba* mi kml k Imn i T* fcvmw k ink rlirti mi Cm EDIA. 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Cmt M ukwnhw ft# |o mMi ymtiiHw ft# t Wm( i l ( Kr^wfy Ljborabry Data L !l Inaftk, ttwin m wi ftrl Pm Vufr--n d Uwimx. nflni 4ifty k mrm and/r ftkd iifIn k bad m***j; (gniaw 6mij mmmjm km (at * 0wn dkyt toft* Wwfcg mattw d tmwnd; tk | i iMa ctfnfwyftjfk if fan Amid W dl Pm ml-- X Hr--tolnfkml InU is k --4# iaekdr kwfUia nkn, lAb# IM nfl < <. AHfrr-- till re --ft itixM ctD rowt, >nftab#yV reset. kawtwrit rrftiH, IMrt lad dettkf Uw, id W-- --rr-- W**y dtfKl won Id i--uaet cd --raw k H[|iy la Am-- 4 y*fnttmml) mm* M d *)-- k |rrt>--iwA 1. HmUm ark iM^k wk A44k <--I 4 further Radm akmtA kkdi Nr-- ukk wd )h#akrai bnk M fun Ada, kkl m Irk, aft--k |V*ki n*a* --if#ir-- aAmf Srmt revChrosAto iW, md pttrmn ml mtmm mmUka ) rftr# Uli-^ ml Pm jatM, ll b Nf*d Pm* tmrUP UUmmkmf Mi a>--Id k --4* i AeAy 4vrk*c tmtrwk. TWm Inn krtvdr I--rlwka *W* vk ftfcM <fl NWd, PMttmm Ikd nut. M>prkd fftj ttmm< mr-- <*lrt-- Nd H*#thirai W*. rn*Vnwftk fJ-- **d ftr-- d mP* nk*lu*M** ftfaM WW *t'r mmmn ***4. N>d *--aty <ii*rfrykjrk tf *--*** tort la *r**M4r Oikf toM U --4r m lr*--wtly m -- prertkad r at ; LI A10935 4 rtimiiin hfcim TWk !* i m<n> br Ikm ta wiw 4k71 ilkr lb Um W At 4na| m4 *" It # Vwfrr M*r**l* m lie-- wit* Id 0 iriififtW fentt****4 CViDift I. IU-* bj kATMM* Or* ml;. *r D.4 **** O-d <U ff*. nn*r |4< Wmt X> Ik 4 U4 hs ) <4 M, i Tttl 4m Wim4 Id I )m JOk U W4> k >1 tnrt X Uu mma wl 4m fmr M (7 4in > U I gm pH X ft>V U*^ #41414 Id 4rM 4mm 4 l4n4il rtMM td Uimttmrnt Lmm< w M 6n nOi 1 md ^v M #mM pwinrf Mm| uiiMM 4c m 4 M |m pit JD Ik l V>4} mo t M mv 10 l^i COWMKJrr TV IMT frf fth)WtJrdADMMl'MKflfDMCTtK DOd (ElJTA) H huilOO* t |*Zt MCI fW< (Hit rtf) Ir* rrporU Hire mcHd tto U| erf pul>kttiiL Mi <4 (to Mfratba coouiftfd in (Hr icttinjDA^ uUr d a i ol<utiH bj- (^nmil ndl them prcrtflj ra|H Ms the wfi {kcmor *rf (hr currftK oMurr oI to wwd, ihr ttwpWin# wcmin); ii rant mnflrtr. It cvmi, bortvrt, nmi erf (Hr am ^ to ]!), JV52. If m mqiriMBf (tut. in net erf (Hr rtcrtrt ifiplmiioa <rf (hit a|n4 10 Hoioficil pftWrtH, three hm olmd) Ut omfr IHon IU) inuacn in tbrh (he dof or hi drUtn tm odmramerrd to Hb u m. CM (hr rcH |4t>nm ttth Wmd ^cD4iin( tmtrd with Co EDTA. b* off duhfata lad ihm idvki In (hr (ur eHUrra i So m am tw too (hm M mnrkrd ifimitic* erf *)inf4<*tk* wnhta men! bur* <rf Ifrmww. In ntf) pitirM M hoa ttroury tt imp trrr determined. (tore ttt ntnidraUr fjhmnwi< at IV acrrtkn WHtinj treiOwM, v> 1 Ucicjt hifh u ID not pmai. Tbrfr *w po mdwt erf tuoktt) (run (Hr d m erf (he dnt(. our m (hrrt e' cm* iworictrrf with (Hr MdtibXhM <rf IV THr Ki|hrrf n ^ Amt erf Co EDTA odraimctrrtd m 10 gw. (mo tw 0 (oiial thh trf)RKn THi* prtirrf ncritrd o turf erf 04.0 |m. orrf o )tticrf erf 22 In rrrr Wvge tmn, (He Mruophtirf rid tn serf i on ondrunfuUm He (nadwint into fotirati Eton Jo torno n rrcTmnf muh'j>4r tnorfinMH (Hrrr *u no rerfror erf iQ HIret- In etfhrf |o(irH (Hr EDTA no* pim tj^rmrouS) tu rirf; Co nrdiiJitm. In ur <i- dnrr, 1 pnlmH hb lentwnal eofmnn n-rfh onmlpic Intern. in what (hr rrwn Co Intb rr * htgb m 25 mg ,TCf) rr^ 0 %m|W <Hm erf 20 gm. erf |!OTA oi odanmntrrrd hrtritrMorfy in 20 nniin, nrf (hr Mfwn Co Inrf no* Hrmgto dem* ta> hH mg /1UU <r. h i oar Hoar. In ottor rifrfvnrfiul khrfire. dr Ni urf Mg chrbiri trrrr oHMittirfrd THr *r erf (hr Mg ctartoir molted m tfgMreioHtr drjrtnw erf (hr imam Co nrf P knk THi H to hr rijreirrf m ritw rf (Hr (xl dm Co ttQ dipUrr Mg (run ctmrfmat*a trh FDTA mtwf ml) hr rimond Iran dr bud) it (Hr cheUu trf tHr KUTA Ortrr tmmtn i^JKitra inrbdrd Mch a*rt 00 nrtirral trrifoOui to du-rrf** okvli nrf r^tvithn to (emwr erfrilr dryuht, Tcforol offrfiratinm in (hr Wm trf wolrf 'tnltrfrfr ormmmt* mdr(4 (Hot EDTA h mdil; corned through tHr dM. THr kw tooicil) erf Co EDTA n ra)H>nrd b) (Hr fending* Hi mrfa nrfng dr C^'WrW inKrml THr motmol n rwrrtfd wnetonged. Alt erf (hr drug ton to om*mtrd k* in (Hr nefrto. Suty t *0% erf (hr odmtmmrfrd drug U |*Mcn( In (Hr urinr olirr (> Hunt, 05 to 0O*g rfwr 25 hour*. THr rnwhrfrf b In (to Irm. DiNrlhotMa morfm rereol v* wnmol VroHntWm rrf (to drug in 0*1) i*fn dnciaig (to lime (hr natmoJ H in (to Hod). 1 Mt r*D<*i4 4* a Vh *4 14--44 4# AmtHH k` .<%-** *'Z . ... aMMi- 1