Document Z82jxb7QQxrE6EpmMzXpQMVQY
A p r il 9, 1957
D r . Sam u e l 3 . N ad le r 1520 Lcu i sian a Aven ue NFew O r le a n s 15., L o u i si a n a
D ear D octor N adler:
I sh all t r y to give you the in form ation r eq u ested in you r teleph on e c a ll of last Tu esd ay, alth ough I am not quite su r e th at I sh all co v er a ll of the poin ts to you r sat isfact io n from the m e d ico - le gal view poin t, 3in ce som e ox th e t h in gs I sh a ll sa y a r e n ot d o c u m e n t e d b y p u b lish e d d a t a . I se n d su ch p u b lication s a s m ay be p ertin en t an d r e fe r you a lso to th e w ork ed ited by F r an k P atty in w h ich m uch th at I h ave to sa y h as been p u b lish ed . M u ch t oo Vouch h a s b e e n w r it t e n to r e fe r to in an y c o n p r e h e n siv e m an n e r .
F i r s t with r e fe r e n c e to th e n o r m a l lim it s o f th e e x c r e t io n of le ad it is qu ite c le a r th at the n o r m al r an ge in r e p r e se n t a t iv e 'sam p le s o f Large volum e c o lle c t e d with ad e q u at e c a r e to p r e v e n t con tam in ation , exten c fr om ab ou t 0. (Jl m g. (ID m ic r o g r a m s) p e r l i t e r u p to an d in clu d in g 0 ,0 8 m g . (80 m icr o gr am s) p er liter . The valu es for the output p er day, as estab lish ed m o st c le a r ly by b alan ce e xp e r im e n t s on h um an su b je ct s in th is La b o r a t o r y , a r e very a.o se to th e sam e ran ge, sin ce th e u r in ar y volum e p e r day is not fa r fr o m 1 lit e r . In deed th e o b se r v at io n s m ade on a fa ir ly lar ge n u m ber of in dividu als in dicate th at it m ak es little d ifferen ce, st at ist ically , w hether on e sp e ak s of th e a v e r a ge con cen tr ation in m illig r a m s o r m ic r o gr a m s p e r lit e r o r the av e r age output p e r d ay in m illigr am s o r m ic r o g r a m s. Th e ran ge of n o r m al v alu e s an d th e a v e r a ge valu e in e it h e r c a se a r e som ew h at u n d er 0. 10 r a g . (100 m ic r o g r a m s) p e r d ay .
T h e se v a l u e s, h o w e v e r , h av e lit t le t o do 'with t h e d ia g n o sis o f le a d p o iso n in g, sin ce c o n sid e r a b ly g r e a t e r q u an t ities of le ad m ay b e h an d led w ith out an y r isk w h atever. Under the con dition s of exp erim en tal or occu pation al exposu re to lead , the ran ge of com plete safe t y is m uch w ider, exten din g u pw ard to the m axim u m figu r e of 0 .2 2 m g. (220 m ic r o g r a m s) p e r lit e r , o r rou gh ly 0 .2 2 m g. (220 m ic r o g r a m s) p e r d ay , o c c a sio n a lly . Th at is to sa y th at in d ivid u als w h ose excr eto r y r a t e r a n ge s fr o m 0. 03 to 0. 22 m g. p e r lit e r o r p e r d ay an d a v e r a g e s n ot m o r e t h an 0. 10 to 0. 12 m g. p e r l i t e r o r p e r d a y , a r e in no d an ger of d evelopin g sy m p t o m s. The eviden ce, of m an y y e a r s gain ed fr o m the exp erien ce of th ou san ds of p er so n s of all age s an d ty p es in d icates th at t h e a v e r a g e r a t e o f e x c r e t io n m u st b e e q u iv a le n t to o r e x c e e d 0. 15 m g . (150 m icr o gr am s) p er lit e r o r day, if sym ptom s of even th e m ild est d etectab le type a r e to a p p e a r . (I am e xclu d in g h e r e an y fo r m o f lat e n t o r o b sc u r e
D r . Sar fcu el B . N a d le r - (2) - A p r i l 9 , 1957
in toxication . I m ean to say th at below th e th resh old value r e fe r r e d to, the in d ivid u al is w h olly w ith out h em ato lo gic o r oth er vagu e an atom ic o r sym ptom atolo gic ab n orm ality . It is p o ssib le th at a gin gival lead lin e m ay ap p ear, if th ere is su fficien t gin givitis to in itiate su ch d e p o sit s, but th is is n ot a sign of illn e ss. It sim p ly m e an s t h at t h e r e i s le ad in th e lo c a l t issu e O u st a s t h er e i s in t h e u r in e ) w h ich c a n b e p r e c ip it a t e d o u t a s t h e su lfid e if* en ou gh su lfid e is available lo c a lly .)
Now the; sa m e a v e r a g e v a lu e s ap p ly t o sa m p le s o f u r in e o f sm a ll v o lu m e , a s
d ist in gu ish e d fr o m t h o se o f la r g e volu m e (i. e . sp o t "'sam p le s o r a sin gle
void in g). Th e d iffe r e n ce r e la t e s on ly to th e r an ge o f v alu e s foun d in sam p le s
of sm all volu m e. Th e excr etio n of lead in th e u rin e is su b ject to con sid erab le
v ar iatio n from h our to hour', depen den t upon th e th rough put of w ater an d upon
a n u m b er of oth er fa c t o r s w h ich can n ot alw ay s be d eter m in ed . Su ffice it to
sa y th at th e sh o r t e r th e t im e o v e r w h ich a sa m p le of u r in e is e x c r e t e d (an d
collected ) the gr e at e r is the v ar iab ility . Th u s, if on e obtain s sam p le s of
ab ou t 100 m l. in volu m e (a ten th , m o r e o r l e s s , of th e d ay 's output) th e ran ge
of. v alu e e xt e n d s fr o m so m e w h a t l e s s t h an 0 .0 1 m g . (10 m ic r o g r a m s) t o 0 . 14
m g. (140 m ic r o g r a m s) p e r lit e r . Th e av e r a ge valu e of a la r ge n u m ber of
sam p le is about the sam e a s th at of the lar ge sam p le s, but an y one sam p le
obtain ed, on on e o c c asio n fr o m a sin gle in d ivid u al m ay be an yw h ere w ith in the
r an ge in d icat e d . Th is is th e p r o b lem w ith w h ich on e is p r e se n t e d in a sin gle
se ssio n of c lin ic a l stu dy in o ffice p r a c t ic e . Th e on e r e su lt is lik e ly to be a ll
th at is av ailab le , an d a s you can se e , su ch a r e su lt is w oefu lly in ad equ ate to
statu 3 of the patien t.
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I S *01" t h e r e a s o n s giv e n a b o v e t h a t w e a lw a y s o b t a in b lo o d s a m p l e s . Th e
b lo o d le Ld i s in flu e n c e d sig n ific a n t ly (in t h e u n t r e a t e d in d iv id u al) on ly by th e
le v e l o f le a d c o n c e n t r a t io n in t h e b o d y a s a w h ole (th e b o d y b u r d e n ox le a d ) an d
b y th e cu r e n t (p r e se n t ) r a t e of a b so r p t io n fr o m a p o r t a l o f en t r y , su c h a s th e
a lim e n t ;.ry t r a c t o r t h e r e s p i r a t o r y sy st e m . (O n e xm ist e x c lu d e t e t r a e t h y l
lead fro m th is d iscu ssio n en d th in k on ly of in organ ic com poun ds of lead , sin ce
th e m e t i h olism of tetraeth y l le ad p o se s a som ew h at d ifficu lt p r o b lem , e sp e -
d a lly fr om the asp e ct of th e blood v alu es). Th e blood lev el then d oes not v ar y
sign ifies!, n t ly fr o m h o u r t o h o u r , e x c e p t u n d e r c o n d it io n s of e x t r e m e ly r a p id
lead aba orp tion in r e sp o n se to a v e r y se v e r e type of e xp o su r e . Th is m ean s,
in th e di agn ostic se n se , th at we can obtain two sam p le s of blood, ch eck one
a ga in st th e oth er so a s to d e al w ith th e p o ssib ilit y o f ch an ce con tam in ation ,
an d if t b e two r e su lt s ch eck w ith in the. lim it s of an aly t ical e r r o r , we kn ow ,
beyon d reason ab le doubt, the statu s of th e in dividual from the asp e ct of h is
o v e r - all ab sorption of lead .
.
So lon g a s th e co n ce n t r at io n o f le a d in th e b lo o d i s b elow 0. 08 m g. (80 m icr o gr am s) p er 100 gr a m s, th e ab sorp tion of lead h as n ot reach ed th e c r it ic a l le v e l at w hich sy m p to m s b egin to ap p e ar in o c c asio n a l in d iv id u als. A t th at
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D r . Sam u e l 3 . N ad le r - (3) - A p r il 9, 1957
level or above, som e in dividu als develop sym p tom s, an d a s one goes up
w ard the fr eq u en cy of occu rren ce of in toxication and the se v e r ity of the
m an ifestation s in cr e ase .
!V
'.
"
Goin g n ow to th e c o lle c t io n of sam p le s of u r in e an d blood w ith out p r e cau t io n s,
th e p o ssib ilit ie s t o r e r r o r a r e alm o st in fin ite. In ge n e r al th e con tam in ation
is lik ely to be g r o ss, and ou r exp er ien ce a s w ell a s th at of o th er s (liter atu r e)
is fille d w ith in cid en ts of th is t y p e . A tw en ty - fou r h ou r sam p le o f u r in e ,
c o lle c t e d in th e a v e r a g e h o sp it a l b y th e u su a l m eth od s (the u se o f a u r in a l,
em ptied in to a b ottle o r oth er con tain er a s th e u r in e is void ed ), often h as ten
t im e s a s m uch lead in it a s w as actu ally voided in th e u r in e. Th is situ ation
is u tterly im p o ssib le, an d th er efo r e we n ever allow 24-h our sam p les to be
co llected fo r u s in h o sp it als. It is p r actically im p o ssib le to avoid con tam in a
tion u n le ss one h as an in t elligen t an d co o p e r at iv e p atien t, w h o, h im se lf, w ill
take c a r e of the d e t ails, by k eepin g a lar ge con tain er at hand an d voidin g
d ir e ct ly in to it over the p eriod in d icated . To give you som e id ea of th e m in ute
c a r e th at m u st be tak en , let m e cite an exp er im en t. The collection of sam p le s
of blood by the u su al tech n ique of u sin g a p y r ex sy r in ge and an or d in ar y n eed le,
a ft e r ca r efu l clean sin g of sy r in ge am i n eed le an d st e r iliz at io n in d ist ille d w ater,
r e su lt e d in rou gh ly 20 p e r cen t (av e r age ) con tam in ation of th e sa m p le s. Th is
r e su lt e d fr o m th e lead - co n tain in g b r a ss hub in th e o r d in ar y n eed le. Th e su b -
;litu iio )f an a ll- st e e l n eed le
in a v e r a g e y a iu e s ab o u t U p e r ce n t
lo w e r . Ilf t h is can o c c u r fr o m t h is- c a u se , h ow m u ch m o r e co n t am in at io n can
r e su l t id e m l e s s e r f a c t o r s , 7Je h av e o b v ia t e d t h is d iffic u lt y in t h e c o lle c t io n
o f sa m p le s fo r d iagn o sis by w orkin g w ith 3 an d D in t h e ir effe ct iv e at t em p t to
su pply su itab le equipm en t fo r th e collection of blood. Th e problem of the u rin e
st ill p e r sist s a s a d iffic u lt on e, but we c o n sid e r it im p r a c t ic a l u n d er 'm ost
cir cu m stan ce s to tr y to co llect u r in e,excep t a s "sp o t " sam p le s voided d ir ectly
in to a clean con tain er in th e p r e se n ce o r u n der th e su p e r v isio n of th e exam in er
o r h is in st r u ct ed agen t. Gven th en u n clean w orkm en in u n clean an d p erh ap s
d u sty cloth in g can an d do con tam in ate th e co n t ain er s w h ich th ey h an dle an d the
u rin e-w h ich th ey void . Sin ce on e is d ealin g w ith m ic r o c r a m s of le ad an y kin d
o f d u st o r fo r e ign m a t e r ia l in t r o d u ce 3 t * k*ign ific a n t e r r o r , fo r le ad is u b iq u i-
t ou s A lit t le a sh fr o m a c ig a r e t t e , fo r e xam p le , h as much, m o r e le ad in it
than se v e r al lite r s of u rin e.
Now, a s to the r e su lt s of the u se of ed ath am il-calciu m -d iso d iu m . It is u tterly fu tile in ou r exp er ien ce to attem p t to a s s e s s th e sign ifican ce of th e an aly t ical r su lt a Qn t h e u r in e an d b lo o d o f an in d iv id u a l wh o i s u n d e r go in g su ch t h e r a p y , If the re sp o n se is gr e at , the ch an ces ar e th at the in dividu al had con sid erab le qu an titie s c le ad in h is so ft t issu e s (th ose e x c lu siv e of th e sk ele t o n ). But even t h is iy n ot a b so lu t e ly c e r t a in in r e la t iv e t e r m s , fo r t h e r e a so n t h at th e e xt e n t o f th e r e Sp on se d ep en d s in la r g e m e a su r e upon th e d u r at io n , th e se v e r it y an d th e r e c e n in e ss of th e in dividu al's e xp o su r e to le a d . In m y opin ion , on e can n ot d e t e r m i.ne t h e g e n e r a l l e v e l o f le a d a b so r p t io n o f an in d iv id u a l in an y r e a so n a b ly reliab le m an n er, except by determ in in g the gen eral ch ar acter of the lead
D r . Sam tjiel B . N a d le r - (4) - A p r i l 9, 1957
m etab o lism at a tim e when it is proceed in g n orm ally .. Th at m ean s determ in in g e it h e r th e ge n e r a l r a t e of th e u r in a r y e xcr e t io n , o r th e ge n e r al le v e l of lead in th e blood, o r p r e fe r ab ly , both of t h e se . Th e r e aso n fo r th is lie s in p h ysiology, th at i s, in th e known b eh av io r of le ad in th e body. T h is b e h av io r is d ist o r t e d gr e at ly by th e ad m in istr ation of ed ath am il, in th at th e lead in the so ft t issu e s u n it es w ith t h is ch elatin g age n t , p a r t s com p an y w ith t h e se t issu e s p r om p tly in m o st in stan ce s, and is excr eted by th e u r in ar y ap p ar atu s fir st at a v er y rapid r a t e an d t h e n m o r e slo w ly a s t im e g o e s o n . T h e b lo o d , {t h at i s , t h e e r y t h r o c y t e s) giv e s u p it s le ad som ew h at slow ly d roppin g n ot a t on pe, bu t on ly a ft e r a b it of d elay , but th e outpourin g in th e u rin e is d r am atic. Even the n orm al in dividu al (w ith no u n u su al qu an tity of le ad in h is body) lo se s m u ch of th at w h ich i s in h is so ft t issu e s an d r esp on d s, th e reform to th e ad m in ist r at io n o f t h is age n t . W hat on e fin ds depen ds to a co n sid er ab le exten t upon th e tim e of obtain in g sam p le s, an d th erefore it is very d ifficu lt to in ter p r et th e r e su lt s u n le ss one follow s th e p r o c e ss b efo r e, durin g and aft e r the ad m in istration of the agen t. Th is is ge n e r a lly im p o ssib le o f acco m p lish m e n t in o t h er th an m e t ab o lic e x p e r im e n t s, an d th en m o st o f th e d ata ob tain ed in a spotty m an n er a r e v a lu e le ss. It is e xact ly lik e an attem pt to m e asu r e r ain fall by step p in g ou tsid e fo r a m om en t and collectin g th e w ater du rin g th at p er iod . Th e r e su lt h as on ly m om en tary sign ifican ce and is in capable of providin g a b a sis fo r exterpolation . Too m an y p eop le a r e m ak in g su ch at t e m p t s an d t r y in g to in t e r p r e t th em w ith out an y kn ow led ge o f the p h ysiology of th e p r o c e ss. Th e ou tcom e, u n fortu n ately, is con fu sion .
I sh ou ld poin t out th at th e sk e le t a l le ad (w h ich u n d er o r d in ar y c ir c u m st a n c e s of slow an d m o r e o r le ss p rolon ged ab so r p tio n of le ad con stitu tes m o st /bu t not a ll, an d in deed, not the im p ortan t p a r t / of the lead in th e body, is e sse n t ially u n affected by th e ad m in istr ation of ed ath am il (an d, fo r th at m at te r a lso , of BA L). 3fiow ever, a ft e r th e so ft t issu e s (in clu d in g th e b lood ) h av e u n d er gon e g r e a t {p r o p o r t io n a l) r e d u c t io n o f t h e ir le a d co n t e n t , t h e le a d in t h e sk e le t o n i s in a d istu r b ed state of equ ilib riu m , an d it b egin s to r e st o r e th e n orm al r e la t io n sh ip s o f th e d ist r ib u t io n o f th e le ad w ith in th e t issu e s ge n e r a lly . Slow ly, th en , o v e r a p er iod of so m e w eek s, th e le ad co m e s out of th e sk eleton in to the so ft t issu e s (in clu din g th e blood) an d th e lat t e r becom e elevated again to an exten t w h ich is p r o p or tio n al to th e av ailab le lead in th e sk eleton . Th e blood of poison ed ch ild ren , for exam p le, m ay fa ll to a n orm al lev el du rin g se v e r a l d ays of th erap y , an d th en r ise slow ly du rin g th e n ext two to fou r w eeks to a level v e r y n e a r ly a s h igh a s it w as o r ig in a lly , i. e . an y w h e r e up to 0. Z0 o r 0 . 30 m g. p e r 100 g r a m s. It is fo r th is r e a so n th at w e follow th e blood ca r e fu lly b efo r e an d then fo r som e tim e a ft e r th erap y. W h enever the blood v alu es go back up to 0 .0 8 m g. p e r 100 gr a m s o r m o r e , an oth er c o u r se of e d at h am il- calciu m - d iso diu m is ad m in ist e r e d (in tr aven ou sly ) u n til th e v alu e s r e m ain low an d w ith in safe lim it s. Only by su ch m eth od s of t r ia l an d stu d y can tee m ak e an y p r ed icton a s to the u ltim ate safety of th e ch ild from th e r e cu r r e n ce of in toxication .
W ith th e fo r e go in g fa ir ly e xt e n siv e co m m en ts I h ope th at I h ave an sw e r e d you r
D r . Sam u e l B . N ad le r - (5) - A p r il 9 , 1957
q u e stio n s. I h ope to get th ese statem en ts an d t h e ir su pportin g eviden ce p u b lish ed soon , but I'v e b een too b u sy w ith th e d a y 's w ork to put th e d ata togeth er . O b viou sly, I can n ot affo r d th e tim e to an sw er en q u ir ies lik e y o u rs v ar y often , but I do m y b e st to h elp th ose who com e to u s fo r ad vice an d in form ation .
Sin cerely y ou rs,
RAK ef En c.
Robert A. Kehoe, M. D.
A C r it ic al A p p r aisal of C u r ren t P r a c t ic e s in th e C lin ical D iagn osis of Lead In toxication - Keh oe
Th e P lasm a- C e ll P artitio n of Blood Lead - Bam b ach , Keh oe an d Logan Exp osu re to Lead - Keh oe