# OAR Box 1126 Prepped by Ollie Stewart



# Document

Number: 

# 23 ) 11-1-14

5 Docket Number: 

# A-83-2 2

Printed 4/18/20089:58:22 AM Sheet 23 of 182 P. 1

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L DA Y5 ORD^Y^5^»p£«p= i LIF E O N LITHIUM-INDUCE DPOLYDIPSIA , STRIATA L *H-SPMJERONE BINDIN

G ANDDOPAMINE METABOLIS M IN ADUL T RATS.. . R.B . HailmdnUD.-L , DeHave n on dM.R . Krigman - Biol . Sci . Res . Ctr . ao dDepts . pitPbonuic&llj M Poychiot . ,on

dPathol. , Univ . Hort hCarolina Sch . Med!;, ; ChapelWnj\) ' 'Hill , N C 2751 4 ••,.

• • . " ' '•• : • • •

" '-jl' " '"'[•'••"•''•..' • "" ' Lithiua-induce dpolydipsi a (LIP ) ha s bee nohow ntto b e increase d i nadul t rat a wh o uer e treate duit hlea d(Pb ) fro s aa y 3 t o day~3 0 o f lif e (Mailoa ne t al. . Science . 201:637 , 1978) . ffhis jSfite c peroanent , i s no t cause db y highe r dose s o f lea dadpinifftexed . 

### s^oFS^'^aa a -'EVIDENCE 1 

### ' THA; ., , LOM-LEVE L DEVELOPHENTA L LEA DEXPOSUR E PRODUCE S TOXI C At3LV0PIAilH0JA . Fo xan dA.A . Bright" . Div. . o f Toxlcolooy. . Uni v o f ,e'hl. . Houston , Y xlm.. . .- , • , \

day s 30-6 0 o f lif e an di s no t du e t o difference s in-^circulifting " reni no r angiotensi no r othe r rena l changes . Lithiuo-induce d polydipsi a ba a als o bee nshow nt o b e dependen t upo na nintoc t ni Qrostriata l dopaminergi c systeo , bu t no t an y othe r oonoarain e sys - \ \ tea . Th e presen t enperioent s hav e narrowe dth e rang e o f age s dur -
. in g uhic hLong-Evan s rat s ar e sensitiv e t o lead-induce dchange s i n LIP , an dhav e als o esaoine dth e functio no f tb e nigroatriata l dop - • oain e oysteo . I ntb e firs t study , rat s uer e treate db y ora l gay - ; 'ag e uit h20 0 og/hg/da y o f lea d(a s th e acetate ) o r uit hoodiu a ... " ocetot e vehicl e durin g day s 3-10 , 11-2 0 o r 21-3 0 o f lif e (birt h= ' d a y 1) . 'A t 6 0 day s o f age , testin g fo r LI P ua s Initiated . Sig - r, ..;•' • oi f lean t increase s i nLI P uer e see ni nth e group s treate dfro a • '".. ' . day s 3-1 0 an d11-20 , bu t no t thos e treate do nday s 21-30 . I nthe..' ; , secon desperioent , rat o uer e treate duit ha singl e dos e o f lea d, . •
. (20 0 og/Itg ) o r vehicl e o neithe r da y S o r da y

15 . A uithin-litie r ; ] , desig nua s use dsuch.tha t eac hse nwithi na litte r receive don e of•• ' • tb e fou r treotcsnts . Testin g fo r LI P bega nuhe nth e rat s uer e co^ ' 6 0 day s o f age , an dth e ooo e rat s uer e sacrifice dfo r neurocheai - •:}

. ca l analyse s uhe nca . 6 Donth s o f oge . Individua l Scatcbar danal-' ; ,, y6e s o f s H-spiperon e bindin guer e perforae dfo r eac hrot' o striat a ? , usin g unlabele dspiperon e a s displacer ; Concentration s o f dop-'"'i-' i • aaine , DOPA C an dHV A uer e quantifie dusin g HPL C uit hE C detectio n• • (Kilt s e t ol. , J . Chrooatog. , 225:337 , 1981) . Administration:o f ;'. , ' • P bo neithe r da y

S o r da y

1 5 cause da significan t increas e i nLIP " compare dt o controls . However , uhe nth e onioal s uer e sacrificed. 1 ; afte r thoroug hwashou t o f lithium , ther e ua s n o differenc e betuee n Pb-treate dan dcontro l group s i nth e affinit y o r numbe r o f recep tor s fo r 3 H-spiperon e i nth e striatua . Moreover , concentration s \ ; '.; , J o f DA , DOPA C an dHV A

i nstriatu a uer e als o unchanged . Thes e datp.' '

. indicat e th e gros s alterations.o f nigrostriata l D A functio nar e ", • no t observabl e i ntreate drats'uh o hav e significan t alteration s o f LIP . Houever, " difference s betwee nP ban dcontro l group s nigh t b e eviden t i f thes e sam e pairaoeter s wer e coopare dwhil e th e rats , uer e " bein g treate duit hlithium . ; I nan y event , th e fac t tha t a singl e . dos e o f 20 0 ag/B g o f lea dcause s o chang e i nLI P o f simila r oagni j tud e t o tha t induce db y dosin gfro m

day s 3-3 0 suggest s tha t thi s . • • ' effec t i s a sensitiv e oonito r o f lea dexposur e durin g - development . (Supporte di npar t b y

ES-01104 , ES-0208 7 an dHD-03110) . "

lashevoice drecoyfcr v

function s suggeste dtliat " P beffect s jsl^h t Ijctlonve'lorrrre s o t th e hlo nIH I an d Tjuiwriiatpri , Conductio nv'^locrr f conductio nanTup s wer e decreas e

org decrease d\ ntnp_j> bgrou puit h If-i a m/s'e c w s 13-l bm/se c IP bv s t ) fo r theft~gr5u p an d4.2-5. 6 a/tec

v s 5.2-7. 0 ra/sec fo r th e Hgroup , .throngy y •"?) Hfifr . toz-*

b *-&ABi£ conductio ngroup s wer e M - wit hrange s o f 68-13 0 p s v s 39-5 9 v s fo r th e H grou pan d125-14 8 p s v s 53-6 9 w s fo r th e M group . Postsynapti c respons e latencie s fo r th e H an dHconductio ngroup s recorde dfor m th e L6N , SC , an d C Xuer e als o Increase dbu ^ increase s 1 nth< - r»rnm>r v respons e latencie s an dthei r amplitude s orfi y occurre dI nth e cortica ) jFEEgVer y functions , latenc y

increase s TTTth e respons e component s ^T"r!t^xi^y"recor3ia

1 nPb-expose drat s appea r t o b e th e "resul t o f a decreas e i nth e conductio nvelocit y an dexcitabilit y

o f th e •'Y/ITT . .in nmrnM" " conductio nortmb s i nth e ON . InfPease s I nlaten c y an damplitud e o f th e recover y response s o f th e retlnogenlcu lat e componen t d o no t occu r 1 nth e LG N whic hsuggest s tha t neo nata l P bexposur e affect s th e cortica l recover y mechanism . Supporte db y

grant s E S 0271 3 an dO H 07085 . ••:•'
. ."•*• :

tXJJ {Report s o f childre n poisone d b yInorgani clead'(Pb )

_-,-^
. ^^j-eversibl e iopalnnent s i n spatia l resolutio n propertie s o f th e Visual] ] systea . Experimenta l wor k fro m ou rlaborator yan d tha t ofjbther s suggest s tha t deficit s ar e confine d t o highe r, • rtj»J^al_.frequ'4nc1es an d preferentiall yoccu ra t scotopic , i n con - '©S^-?? j photPP^c , level s o f luminance
. Thes e change s hav e bee n , < =PSfiart?.ttOc^ccu ro t oi l level s o f th e visua l syste m (Fo xe t nl.„ : Tox
. Appl
. Tox.a0:449.197 7 an d Neurobehav
. Tox.1:101.1979 ; Fo xan d Sillman
. Scienc e 206:78,1979 ; Bushnel l e t al.
. Scienc e 196:333;-r,.,. ' 1977 ; Impelma n e t al. , Heuroscl
. Abs.8:1 n press,1982)
. T o deter-
. '. ralne I f th e spatia l resolutio n limit , visua l acuity , o f th e adul t rat' s (10 0 days o f age ) visua l syste m ua s altere d followin g low-••"; : leve l neonata l Pit exposure , electrophysiologica l and^psychophyslca l studie s ttere

conducte d a t aesopl cen d scotopi c.levels.o f .luminance
. \ Female.neonatal.Long-Evan s hoode d rat s oer e pxnasaLtaJBUCAC-no'*' - 5 -Pb ) fro m oarturltln n t n HP»n1n o Tdays_ft^LLjd a th e m l li e o f dams •"•} rnn^mttrtr, » 7t

P h jcetat e Joiujgi)^!^^lHJdftns."^nec>er^a ^ bag ; i gSer^reversa l jgrjJjaJLeyfl& d potential s (tempora l treo . UTfflTHT T; • air e recoroe a i n chronlcafl yimplante d awak e rat s an d use d t o es- ^ i tlraat e ^uaJJjfuU ybya codificatio n o f th e extrapolatio n tech- ' .': ' ' nlqu e (CampbeTToii a Haffel
. J
. Physiol.207:635.1970)
. Visua l .' ; .acuit ypsychometri cfunction s wer e obtaine d utilizin g sine-wave ' /grating s (0.1-1. 3 c/deg ) i n a conditione d suppressio n paradigm
. . .'
. . Result s I n contro l an d Pb-expose d rat s revea l o clos e corres - ' .pondenc e betwee n electrophysiological!? , an d psychophysica l l yde - ' termlne d spatia l resolutio n limit
. Th e oaxima l spatia l resolution ' ' I n contro l rat s aa s approx . 1. 3 c/de g unde rscotopi can d oesopl c conditions.:Thes e acuit yvalue s ar e I n good.agreemen t uit h thos e ' o f Birc h an d Jacob s (Vis
. Res.l9:933.1979 ) an d Lennl e on d Perr y ( J
. Physiol.315:69.1981)
. Pb-expose d rat s exhibite d a Z5-S0 2 decrease"l" n visua l acuit y"wtxtt greate roencit s bein g observe d 'WceipteiftoirnrrTOia n roesopic, conditions , uecreases m spatia l res - •=o?uLiu n utrre-tmityVS d a t al l Willi ' nreqmriiple s greate rtha n 0.2 5 c/de g I n Pb-expose d rats . I n addltig p to . the.'''"'ro»ep H p?p? jwpii
. tudes fwhU h accoun t fo rth e decrement s i n spatia l resolution
. In crease s in~P2~jrmr~wrjratencie s were observe d i n ih e P b group . , [ ' ines e dat a provid e evidenc e tha t IOH-ieve i neonata l > b exposur e

. produce s toxi camblyopia
. Theyals o exten d th e finding s tha t th e scotopi csyste m i s cor e vulnerabl e t o th e toxi caction s o f P b tha n th e mesopic/photopl csyste m an d provid e furthe rsuppor t fo rth e ; ide a tha t al l level s o f th e visua l syste m ar e affecte d b ydevelop - " denta l Pb exposure . 'Furthe rexperiment s t o determin e th e specifi c

. s1te(s ) an d mechanlsm(s ) o f actio n ar e I n progress : Supporte d by grant s E

S 0271 3 an d O

H 07085
. CV S

3 CENTRA

L EFFECT

S OF L( W LEVE L DEVELOPHENTA L LEA D EXPOSUR

E O N OPTI C NERV E CONDUCTIO

N AND TH E RECOVERABILIT YO F GENICUL0C0RTICA

L • . ,. ; RESPONSES I KHOODED,RATS
. P
. Impeloan"
. C.L
. Lear a

. R
. mison^i v von d D.A
. Fo

x(Spon
. B
. Brooks)
. Div
. o f Tox
. Univ
. Texas Hed
. * ' • Schl,
. Houston , T

X 77025
. Long-ter m effect s o n visua l function s 1 n rats , followin g low leve l neonata l lea d (Pb ) exposur e sugges t tha t clinica l report s o f Irreversibl e Impairment s I n spatia l an d tempora l resolutio n propertie s o f th e visua l syste m 1 n childre n ar e partl ydu e t o change s i n bioelectri cpropertie s o f th e opti cnerv e (ON ) an d i n recoverablllt yo f visua l cortica l responses . Followin g neonata l

. P b exposur e latencie s o f th e retinogeniculat e an d retlnocolllcula r response s o f flas h visua l evoke d cortical , potentia l (VECP) I n adul t rat s ar e Increase d (Fo xe t al. , Tox
. Appl
. Pharm
. 40:449 , 197 7 an d Neurobehav
. Tox
. 1:101 , 1979)
. Latenc yincrease s I n thes e pathways saa

yreflec t a decreas e i n th e conductio n velocit y .an d excitabilit yo f th e O N fiber s sinc e postnata l exposur e t o P b : produce s hypoqyellnatlo n an d a decreas e i n fibe rdiameter s o f th e O N (Tennekoo n e t al. , Ann
. Neurol
. 5:558 , 1979)
. ^.Conductio n ve Joc1t1eS-JUldJJlcQnax yvaTue s obtaine d fo rth e thre e U N conduction ' groups'an d th e postsynapti crespons e latencie s wer e measure d i n electricall yevoke d potentia l recording s fro m th e LG>L_5HnerlP r

- CQl'llcufuTTSCT ran d th e striat e corTeJTTtX_L1 n aduftcactrq l an d Vp"iV'eate d iong-tvan s hoode d rat s remai e rat s were expose d t o ^T D lOV'n o v.)

fro m parturitio n tp'weanin g (day s 0-21 ) vi a th e mil k o f dam s consumin g 0.2 2 Pb acetat e solution s (o rwater).JGec trica l jatote d rgcover vresponse s t o doiMe-Julsje-jAlmHlaJdMLftf, , 'lipnliw wrpcorde d becaus e th e similarit yo f electrica l an d 23/ 1 ElffiVKWA L DEFICIT

S I M KCNKEY

S EXPOSE D T O IC W LEVU S C F LITi D SIKC E BIRTH . Debora h C . Ric e 'an d Steve n G . Gilbert " (Spon : rtijrj-i.. • '•• j

f B . Heis o ). ' Itucioology Rsssarch Division , Bureau"o T Otgnical " , • Safety , Foo

d Directorate , Haalt

h Protectio n Branch , Health an d Welfare Canada

, Tunney' s Pasture , Ottawa , Ontario , Canad aKI A 0L2 . tonkeys (Macac

afascicularis ) uer e dosed orall y fro m birt h wit h 0 , 50 , o r100 ugAg/day o f lea d es lea d ecetate . Blood lea d level s peake

d a t1 6 o r2

2 ug/d l b y 100 day s o f

ag e fo rth e two treate d group s respectively , an d decrease d afte rMeanin g a t200 daysC'o f eg e t o 1 2 ug/d l i n both groups . Blood lea d level s fo r oontro l monkey

s vere always bslo wth e leve l o f detectio n o f

^h e analytica l procedure (5 ug/dl) . (Bie n th e nonkeys uer e approximat el y thre e year s old , the y vers teste d on atKO-choice discrimin atio n an d serie s o f

reversal s paradigm . Di e monkey s face d a pane l o n uhic h uer e atub e fo rdeliver y o f frui tjuic e and two ' clea rplasti crespons e disk s tha tcoul d b e backli twit h variou s stimuli . Ot

s stimulu s displa y consiste d o f atup-dimensional for m (squar e o rtriangle ) an

d colo r(re d o rgreen ) o n eac h disk . Durin g th e firs tpar to f

th e experiment , both disk s uer e alway s backli tuit h red , an

d th e BDnke

y ua s require d t o respond on th e dis kdisplayin g th e square i n orde rt o receiv e aemai l onount o f appl e juice . Th

e dis ko n whic h th e correc tstimulu s appeared ua s varie d randoml

y fro m tria l t o trial . Hhe n th e monke

y ha d learne d th s tas k(a tleas t9 ou to f 1 0 correc ti n a10-tria l block) , th e correc tstimulu s becam e tli e previousl y incorrec tone , an d th e nanke

y ha d t o relea m th e task . A tota l o f 20 suc h reversal s uer e performed . Fbrth e tu o followin g tasks , th s for m an d color s wer

e displaye d independentl y o f eac h other , uit h on e dis kdisplayin g on

e colo ran

d form, an

d th e othe rdis kth e othe r possibl e pair . Fo

rtt e second tas kth e monke y wa s require d t o atten d t o th e color s c n th s dis kan d ignor e th s form

s (initiall y re d correct) , whil e fa rth e thir d tas kth e form s uer e th e rele van tstimul i an

d th s color s irrelevan t(initiall y triangl e correct) . Twent

y reversal s wer

e performe

d c n each task . Fo r each task , ther e wer

e monkey s i n th e two treate d group s whos e performance

s uer e outsid e o f

contro l range o

n th e reversa l eerie% , takin g lange rt o lear n th e reversal s an d makin g mor e tota l error s tha

n controls . 

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