Document n95vpoaX4zX2N6zO4Ox1rZqG8

r-rwu^rT] iL ataaiaaM HARVARD UNIVERSITY 1 >:jjflii*''iiiii fri?rftirifc(i u\ -<w M Mitl#*! * #*?. |H| July 20, 1967 Don C. Fowler, Project Manager International Lead Zinc Research Organization 292 Xadison Avenue New York, New York 20017 $ Dear Mr. Fowler: '38? I an enclosing herewith an application for continued support of the project entitled, ''Study on Biological Basis of lead Intoxication" under the direction of Dr. Bert L. Vallee, Professor of Biological Chenistry at the Harvard Medical School. This request is for a or.c-year period beginning January 1, 1961, in the enount of $S2,6S3.*0. i This explication has the approval of Dr. Elkan R. Blout, Hesd of the Nrpsrtr.er.t cf hicloglcal Chemistry of the Harvard 1 Medical School and of Dr. Robert H. Loert, Dean of the Harvard Medical School. If there ia any further inforsatlon you desire, please do call on ae. Sincerely yours. i HCK/cj Encs. Henry C. Meadow Executive Secretary A  pwg"; i I'lwpiijpuiipu1 iinpi Wm LIA12358 ^ ,4StaeissaaaM fmair h A ^PKPOSfiD BUDGET FOR STt'DV ON MOLOCl CAL j>AMS Of I-PAD IKT0X1lATIfV- Personnel Research Associate, full tlae Retirement, social security, etc Harvard Cosmosite Bate, 161 Two technicians, full tine Harvard Coupeslto Bate, 9 5/41 111 ,000.10 2,140.DO 12,200.00 l.lBD.so Oi;p>icaja. and C1 .ussrs 4,000.00 Aniaals liic'.ude* purchase ai.d mau.tcnance, special dirts, plastic cajtes, etc. Tire i li.ciiidt, v. o;. i rue t; . of lij;h*^* c,,it-je i racis fr.r s t > t' r i ! c rnortsr t r.s 7,100.00 *4 '.no t r*<>) i n e i .. Je rri.Mni t j t { ' I al Us i 11' t r l i* I?/.* li.< ) *. * \ * * i a '. k ( rlMi, *. r*h* 1 ** r } . * i t r , ting v' ( A'^ui f r. t n* t > r- U,r 4< . * ` J a 4 wpiir^ N 543.01 NMnvBPIII if IIA12359 A . -* -i HrA-mmi-;,,.a Itr.iwiflniilftiKfAin MHO PWOJSCT WWW X**U* D*t#l Auguat 1967 PROJECT BO. U-9t T17U Study of th* Slological Baml* for lead IntCKleatloo fRmoUB mufTITICArW ULC-16 Study of the ilologleal kill for Lead Intcocleat Loo CtarrWACTOS iui-rm.nl Medical School ctnqtarr ccarnucr January 1. 1967 to P*c*^w 31. 1967* $3*,B6f.ao CHOUiTTO ILPUtota (to July Jl, 1967) #77,163.00 1968 pnopoetp os cormcr met 152,853.10 1968 A1CTK1RIZATICS 1967 A Prior Awthoritatloos ttir fitted 1968 Propound Authorisation Ubde*lgnated Seaearch Authorltatloo 1966 Proposed or Cootract Prlco bo o* l52.85J.kO aoo* I52,95)<k0 HAWQtr APPUCATTOSS To all l*d auttU mad use*. O&JCTIYI To provide fuadaoeatal understanding of the toxic node of actloo of lead la biological Materiel* and to further the uoderstaodlnd of the netoboll** of lt*4 tad BKbtalmM of heavy a*tel detoxification la general. TOtWlI KtVlW r Current gTiVim The 1 tolat loo of Mrtallothlanela froo nbttt kidney* bo* bee* a-S'cved *r*d n hoe b*n deonot*rated that lead tt associated with tht* protein when It 1* purified froo the kidary* of lead-Intoxicated rabbit*. A leod intool cotloo etudy It olto belog carried out using o pooy. Detailed exp*rtoreto1 eoodtttona for lab lb It loo of the ale roorgar.l mo, leiodopeeudanorom mpfteroldem, by leod acetate bare been established. A tpeclflo letlon In tetrmpyrrole netabollao through which oan^aaete and lead Interfere with tynlhetlt of both beat aod bacterlocbloropbyll bat been identified. Tfcl* establishes that leod toxicity caa operate through the w 11-kaovn oechanlta of Metal loo antagoelsa. Current studies new rang* free Investigation* Intended to Laprove the analytical chealitry of lead, through Interact loam of lead vlth enmyaatlc and oonentyaatle protein*, to effect* of lead upon the artel ell mo of nicroorgaaitas, and finally to love**, lgatlo* of the Intoxication of lead la higher mfeclem including mmaalm. 2. Projected *,mr-b Atteapt to isolate liver ribonucleic acid, Milch ha* been mbovn to contain nete-is much a* chraoluM, nonganes* and nickel, ahd deter* tne If leod lnternctm vlth tht* aaterlal. Attempt to determine if lead dimplace* tine fron liver alcohol dehydrogenate, a feasibility suggested by the In vitro eiperlaent*. ) Vport* }Hj s 4 *Tfri.gr* mm a*|ort* - from 1/1/65 to 7/20/67, three, lomt report covered the j-rlod 6/1/66 to 7/1/67b, Pr.^.em^ . hvrtr.o bnerr nm s t u d t o s u o u c j c a l mu or ic a d lima:.*AT ICS (received August k, l'*>/). c. Wi-rm QteteneM . non* /. . , v HU'lfSX.' .1 'UP -.u l|iMJ.lgJI^^ ' wu"wjmm9ip .aterito-'-A. -biitmr- 1.- >mm iniTarMMMAiMn^rtM.n..* i iMfiHUin nr aiiMiiMifliiiiiiii tarrtuffMBT o t iw II Mien Prv&ZctUx - not applicable 2. Cooaeawr (valuation - d o * applicable J. Uc c mId c Aetlvltle* - DO* applicable 1. M*ctl DO* applicable 3. Publication* . nzic * d o m k. Dtvalopacat Aeaoclatloe* - b o m k o k mc neww H Market Go*1* - Dafaoae of eoeb m TEL, palst, can aolder, pr**stlp u mv UI b~nll*atioo* of tootle reaction. Expaod lead m Into area*, aueb u auto body palotlafe ebera all*(atloo* of toxic basarda aitl**t apalaat to*#. 2. Accllcatloca aad Wtrtat Talu* - 111 land MM. 3. 81f of Xtrtt Defeadlce Application to all laad aarfcat*. b, Competitive Threat - Pefeoalvt apalBCt co^etltlce and 1*#U reatrlctlon*. gp^^ww^iM|in>"np.ai.' w ^mppw i "pwrmummBwtaan. "V'1^ LI A12361 W LIA12362 ISSBS^Kf n.rmm m*' wuj -yy- tw ii e i .mgpf n ................. ... ... .. . nmmaii wwfm 'aeeem' 1 MPWwyp^fH^ip^ ' ^j, pi|ip^ppj|ppwp^iig^ppww>pBp|| tmmsmm LIA12363 iiiMitif*hiitfiiifftiiWinvti frii iiil'faiirtWiii lifim MatifiatM Mfltitaiarib Nr, Don t fowler July 70, l^A? Tbc grras effect of lcav. on porphyrin metabolise In Ran end other higher fome cf life i well-known, manifesting either in eneeia or as an abnormal excretion of porphyrins r their precursor*. liowcvrr, the specific sites of action for 1.*i have rot been clearly dt1 moated in vivo. The studies with Rhodot'Seudo^onai presage both tht-'TocalTzetion of the d* feet'snsTltJi e vaViTTlea that may effect it end, perhaps, he employed diagnostically. It is rewarding that the metabolism ci a microorganism seers to serve as a suitable test system, besting out our anticipation*. t Previous Progress Paperts have described several f cur in vitro investijatiocs af potential interaction* of lead with cn.cia 1 earyuatic systems. These efforts were stated to be eriicratory siaie it was cur intention to celine.it' biclrglcsl systems which might he sansit.ve to lesd i_n vi t rc as a prelude te investigating possible in vivo coucte rpa'r t"s, which might predict the chemical nature of 't^e site cf actior,. Recently, we have found a very good ruw If of *uth a syater, lipo.ride <Wh vl t o< " -. -thi* i- j * * r t ; n , r a t' load iniotait* eery strung!;, . i > 1` . criywe, pros osar i * t;.r-uh n.lfl.vdryl l'r.Vagr* -t t'.e active eniyeatlc site. E cmiraticn cf the influence of coemymes and substrates on the lead inhibition, and it* reversal by fPTA, Indicate that eh** should be a post Interesting and important mr** for i further of. Jy. a? intend to explore this r,,,re thereugaij *o * mi reorganises and higher Icnn during the feeing month*. It *: -.y br c-i` mtes'sf It , jint <at t.ist our .rtren; i. 'in ! the Viclcgicel has i * for 1 ad IP t'* ice 11 on new r g r* r.a i r.. e* t gx t i c-,s ilt-led t; impit'C thf analytical chon, i f) cf leat, t'-rei;' > r. n t r 1 cn of lead with eniv^atic an l !, ,( /; t . . Jl'te.,*, . f f-< t-f "f lr*j vp-'i the metatnl.tr o` '<:* .'tfii.fr-., .-<J fi.(.ll/ u l*i ; * 11 ge t ion o' the in- t I . ! .1 X I' t. y I leal If h I g ' e i 'J.rCH' i C f uIi 1. g m <s 1 * . !-vf '. ng if" (.! !i /tn' V-J !.P g-.tr rd *; i f h'. with ' fleet', r. I ir. %.ih of t'# nrehi. r.e u.ve. -.tt ' of t*: *p;tnth n< aliO'-S i. to *#le t lot me' -"{crl'trtt S ) tl'C r 1 t 1 11 1 Ccnpleslty Which ; r<s' vutt.hol; g > r t.n- t">|ge *t hard. lh* brta.ith r-{ operations ml*'!- in t .ti `.h-sr sne rslsted areas sboui'i prove i.'.uro I', fy A > eh Sag CLS > this wtfl tt-r.tl.wes \ li.'aiSy, t!` writ |* *( a Msg* where l* aovJJ appeal ,-W V'H 11'