EPA - REGION VSDMS

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Jftitv:,

THf 1970 COrrtfGHT LAW

THE HARBEN LECTURES, 1960

THE METABOLISM OF LEAD IN MANIN HEALTH AND DISEASE

by

ROBERT A. KEIIOK, M.D.iFiY";i the Kfttcnnt: Lrtbor.itorv in the Department of Preventive Medicine; r.:i;l\^A * * • • M !»' * '

I'i It^tri.J lic.ikli. Colle-m- of Mfdicinc, University of Cincinnati, Cincinnati ,Ohio, U.S.A.)

LECTURE 2 (Part 1)

THE METABOLISM OF LEAD UNDERABNORMAL CONDITIONS

In tic Chair. R. I*. GUVMEK. T.D., M.A., M.D., K.R.C.S.(Oi}i'.:i[i-Ch<;irni'::n c>f the Executive Ctinmnticc of the Council;

i/.'.-cl iii t ; ; i t< ni;> of tl.i. prectdnijj K-clmv,is a iCi : ia ik . ; ! ' l> stable atid un:f . MI: procc-s*.

" n b i i u M i i . i ! " Nic - tubc / l i sm (.5 leu-l . it isdcfiiu- the- iiHMiitM.: of tlmc ;.- our usitj:c, and to cstabl:i:l sunn 1 of the pre.<^iit;;ti''ii wli icl ti t - > \ \ . 'J'lx'ii- can be l i t t l e dmtblh' l i ; ; \ i t i i: c! k\iJ in nia;i i< a f i c c t c d

s.'.rv t

i- Uth.it

term.^ l i t l t c

My cer ain tyj1"* ot disease. Such efu-cts.htiv-cvi.: . h.ivc IK-I.:I c\plf>i'Cil but l i t t le . ;mc!i.'ictitJoi- will be m;uU' C'f them only inp.:ssiu». \\\- must al>o omit a ful l discus-si'.'ii of t l iCMpiut ic jimcediircs designed to"mobi!i/.i;" le.icl from tin* budy. in"favourof a brief statement of certain facts. Thedistribution of lead in tlic tissues and therAte of the excretion of lead from the bodycan be modified considerably by the admin-istration of dictating agents luch as British-Anti-Lcwisitc, deri\-ativc$ ot cthylencdia-minetctra-acclic acid, and certain othersimilar compounds. 11>» induction ofspecific metabolic disturbances such astliose occasioned by jb» increases anddecreases in. intake orcaicium and phos-phorus, or those involving drastic changes

in the acid-base equilibrium of the body,exert litdc- or no clitct upon the rale offxcretioii (if lead or o:: tiie conccntratioii i•!lead iu t!ic blond: such minor chraicrci iiithe metabolism of lead as arc seen in a-s^-ci.ition with these procedures are no preaUTor more prolonged than tl.ose occasionf.iby tiie accompanying change* in tin.'throughput or temporary increases in out-put i'diurcsis' of water.

Abnormal lead metabolism, as defined f :•:present purposes, is characlurintd byquantitative changes which result froiiiabnormal, that is to s.iy, unusual, conditi-.ui>of exposure, as these ary induce j by a wid-.-\-ariety of industrial operations, and also byconditions which occur from time to timein the environment of the home or else-where. The emphasis upon the quantita-tive aspects of Hie matter derives from thefact that" the pattern of the metabolism oflead, as we now JcnOw it is modified butslightly, and often not at all, by grossincreases in the severity of exposureor in the rate of absorption. Tin's isnot to say that there is not somesubtle change in the behaviour of thelead in the tissues, or some intrinsic change

101

ru ti->:i '^ t« li.-prt'v. nee of Ir.id. when I A1 i'ntoxit all <nuistii.'.v 'i he i.-iluu- tit iinv such incchan-IMU is unknown, but it is cle.u1 thai itsactivation depends uprm the presence of anadequate coneenliMlimi of lead in thet i ->nc> -.presumably at the riyht p<mi t or inthe pitiper sl.iU". Tims to all prcsci'tappCMi'antvs, tin- metabolic proci .^ .^"o-elated wilh saturnine iiitoxit.ition thticii

hum the normal piv.cvxv\Vi',e;i the rale "of the absorption ot had

is increased l n \ u n d the range ties'Tibed inial arbiliMW terms as ' rvmiul , '

i- in the vale (>[ the

onl

unr simthere- is ;i proinpt flu( \crc- l inn <•' lcui'1.i:icr'-,i"t- in tht (nitp;; M'\v.idrd llit- ix- i< i

in

v. ith antin- b n d .

I ' t ip.ti i nu-\' ;;pp.-.'.1atii'>>. I1. !<'.

a1".- iu tl , ' - )-. ,;J (.tlfino'i'-li'.i'.c-,! .; hill

s i i i i anhe ni me: ul thevi-i.itc;!t iu-ni of

I.I'.IT inli of ihc. i r . t - i in

.^v l at a1-.t.1, imif'irm-

>t iimi.-. therei.. she rat-.-

1 VI t ! , ( - If.idr , ' ip . . i t i i in of.. L! had in

U-.id content of th; b l - ' -M It the ithe l.iU of abyuptio:; n numtsufittieut level anrl with S1.:;;.i'.y o\ cr an uppritpri.Uo pCTi.vwill be a jirt'^rftvji c in, i< ici the mv.iary exvr r i i 1 *: . i.l 1«c -nitcnt (A tin: biv.ly, .01.1 ••• ^the l.i'.U-r. in tin- c 'Mit .* . ' ! ! ; ! . ! 1 .tlif I'1-IUU.

1. iiir iNcr.STios (»r IMP 11C t i K ' i J K.V/MTiHtCC.'jff / ' ' ' f t .

*1"1 •• fnt- "i iii't ' i" '1 ' 1 1 v tl •

res"tlt> of a >eri'- <•! b.il.mt i. i \ p - i n.icnt.-.in whivh each ot .1 s i -nt- "' v • .1..'. U-.iUhy.hunian snbifds ha^ taV.rn , , . . . ^ p u - m - solu-tion of a lead salt in a V n n v . , , . j•: u. ;n\ \\ Rheach meal on every >nt i . tMvi . i'.i\ o\^-i aperiod of months 01 yi . i i 1 >

Briffly in describe th-. c vpmnu-nt.i l pro-cedure, intelligent and r<. liable >ubjectswere seleuted", after .1 comprehensiveinvestigation of their prc\ions and currentpersonal, physiological, and medical status.In u preliminary scries of observations, eachsubject was instructed in the collection ofduplicate quantiti« of everuhmg eatenand tlrunk. including medicines of any typetaken at any time (onlv with the knowledgeand on the advice of the supervisoryphysician), and food or beverages takenifiiyaiwjtiii/, ttuu *wi>u ui »c* ci iiv^" ^tiNFitbetween meali; he was instnicted furtherin the techniques of collecting all urine and

*Vi.'.'v b'lth ntid-.-r the oiu.n.ir- c . ,' , • • ; • ,i-l i.L'.i':\ Lit- .ii,.' i:. I . . - c :;•»• • ' ;,..

commoiily iiil;-rnipt or ino-hty thi- c . , . ' - , -routine^ <•( olnerv:isv h^-a l l i iv p, •. •..,;\'aric;u; clinical olisc: vat inns we., ;: ..•;..

sary t i iuc>i. at \vhi';h time unpin ..-..-saiiiplt'i of blood \verc ubt.tiiucl hy. \ i - i i i -pni icUi ie tor analysi-t. A Ji.iu li.-^-.i:,.; t ! > . .food and bevi-raycN eunsiimej. ;;'. ' \\.cuuntiirj: brieHy t t i f : m,; t ini- ,md a:./ i . ; . -nsn.i! uetivilit s of thv day. \-.\is U;i ' ] . , ;the pri\att' infoimatio;] n! ilie pi r . , ;•> . •invi ^tiiiator.

At some pr> ;nt in ihi- exp f i i i 'regimen, iit'lcr ihr (•h: , i i , ie t t i i i i ' ics oimn;i.il mctaS ili^tn oi Ir.ul h.;d lnvn <lishrj. the cvpcnim nt.il i:ii;».>ii '»n o'.\'.MS initiated by pr-i\ u ' i ' i ^ tiu >•\ver-Uy \\ ith i;l small c Mthr desired (I'.i.mlity oia;mctKi< snhilioii h id bt\S'' a- to facilitau- the in^u-;dose wilh each meal.

Flirt IHT dt taiK of pi ' ict (.Inn > \>, r . - . - l ,have been i-'.'rlected bv i \ i i i r i ' , - iK ' ' . i u - dr.tit h.- elab'.rated ..t tii:< t::r.v, rv.-cp1. !-•s.i\' t'n,it eveiv eliort wa. in ide *..•• • .• l i ' i i iu. it . '

tK-i'.i-

in the perfcivinaiicv ot tn-.' -nh;-!.1. ..>•..} i:.lh" handling tit the anal/ti-.,.1, \ v o i i . . Nodoubt, errors ot sampling. t-ncti . i l!v If* >y.concerned with duplit-ati t-n e! the t • '.'i e m-snmed. occurred rrum ti:n- t.- I 'M.- -nitthere is httlo reason to <!<Ml^ thai th'^v ofp'lMtive and ne;.Mtive si-jn h.i\i t"inh-.1 t>e.meel each othrr thnin1.: t'.i p; i!Mi,;4tvlperiods of obwrvntion. l . i kv^ i - - , in .s l \ -tieal errors \vero iiievifiibh. bui ( MutanteVicelciiii; of the analylieal pn-.-i-inn inse\\'ral wa\s ijavc rca>unahl li»nr.mi.i- thatthese would not be cunml.itivr (,r >ystenvatie, and that errors of pn>it i \ f and );•. j:a-live siyn would occur with appioxini-iielyequivalent frequency.

In the first of such experiments afterbrief examination of the' normal metabolicpattern, one milligram of lead was investeddaily by Subject M.U. (in addition to thatwhich occurred in his food and Inn-erases).over a period of 1.456 clays (became ofcertain fortuitous omissions, the total quan-tity of lead administered in this \v.iv was

102

i. .-•.-. : !•- I I - . ,. h

,.;.::..:y t-:, !.:;. .„* ! - • e-' ii'v t ! ; ' • _ . ..' :-.M';r t;.p. t;,./.i : . . 'd ; fv t i , > . d..;!y].•.-.!!:!;> r -o -c i i .

.:ti M.I W'TV ::u.'.ie

'.. ! at O t l l f f l i .U ' j -. l i s p i - d'lnlic.aU': : , t . in d by VL-I,:.;. di..ry l i n i n g t!,>.-

; i > ' i H l ' *.!. aii'.i ri;.;;.!,•.• and any mi-

t . : . i V . V. ,'i«i k l p t fn;-

r.aa:::~ >•

i i'\' "

i iuM-!^ - 'I he- ol.<f:-v t:'i<,;;, WL-I' i t ' i ' T an a-M'tiou.-.l i!Yi d a > - » a f t r

. t ' . v , . . . . . .K,,-. t V:ainatcd. at wl i ivh ti:i.f l l i c - expcri-},;tV,t \v..s concludi'd at tin- \\Mi of theSl 0\i"i' t l lC pt-riod nf eiplit years, additionalcxoerinit-nU of this typ;1 were conducted.in Vhiob cuinpuiahlr infonn.-.tton was oh-fined as to thf )xspnns,.'S of three otherc 'v,,ciii'K-nt.ii suli jcuts t. ' the daily inpcstion,f 9. 3. and 0.3 milliitr.tms of loud respec-

tive' v ae aqueous solution.- taken with thrnr '\' ^Earlier cxpi-riinents of this generalt'vp"v.-eri' carried out prior to the develop-r'.eV.t of the analytical method nn\v in use

in the Laborator\-. Tlr.- r.^-ilts. \vhil-:siiv.ilar. a is.1 not strictly en:n:i.ir.ihle. q i i .m-t i t . i t i v f l y . i None of these was sn prol-m^o.!as tlic first, each hnvin:; hern ilisi^iu'J.primarily, around a question that could b^answered in a shorter jieriod of time. More-over, the patience and endnrr.ncc of eventhe most imperturbable and complianthuman subject has limits. It is nei therpossible? nor necessary to speak of the in,mydetails of these experiments at this ti.no.nor to deal with the many experimentalfindings which have been or arc to be p i t - -sented elsewhere. Instead, certain portionof the data have been assembled in t abu -lar form or arranged yraphicalk. i:i

Table 17Lead Intake and Output in a Healthy Human Subject (M.R.)

• i , : , . . . . , , U : ,H ; , —————————————————————————J. .-- !•-...! s.> i- s-acco^five•ci . u:-..!»'i:-i\! o'.:. i, - ,. . . i . ! , . „ . . * vn'M*

• ' • ' •"""- ' -L" o! 2r I*--..-

;T •eii;1:'-'* \.',:c!,ey;v..r. :.., n^J ; Conirol Kri • i ... ... 1

. i : ('::.• . iv ;•; t<>• i;-..i.;-. I.' e luni i i . . : • 'j-f5. p^ri.^ —. jy.-t' ::..•.'.(•. i t r - T ": • • • ? i :b : - - . i t ;i'.;i i- 1 n:c. -.•' l-.'(id ;;- K ...'1 n:c -.ate 1. ' . tic..! w . - : X . _ .\i- ' of k-.i 1 chl.-ridc i:: *-''lu-.;. (->|'-i.;..!!V t:. '>.• ( lion, ink-jn daily i:: u >jvi --:: i«: t ' .v i • K! t. • • ; ; • | of ( > • . ".:;:} mg. ea-.li \vi:h

"''•*••' -• ('••''•'•'• • !'"•'> . !;•.-.•_;.- 3: -ill*. t:..,t th-.-v of.-;: IM-..;- '.- n-K".- t" -J;.. t:.. .p.-.il'.i,̂ .,\! ;

l . i f a \\ ; * • . • a i . a 'y - : i"' . : i . !•.':'. t . > i i - , l a ! i t (

j..,\\ ^ tvei^i ' iM ii- . G^- ' " ii *.•/ ,'.- .!"'i!Mm i* tl'.it,\.:\i'* c r>: >\^t'.'iv.- •. 7

.-!'!-•: ,i:,d ne;,'a- . ;- .:ii .!:';v-ti\n, lately S

* •

f\pvri:r.rnl.< after ! 9ivnr.al inctabnlie ' i

:]-.'.u!\.a<int:esti'a ! 10

::. i'uU'itiun to that ; '•x! aii.: be\-era?e5;, " j ll

t'..i\'s because of i .•.:«. "tl.o total quart- ( ia

l.cn:lInwsted —

MiuVnnv* •

7 -'2..'.

3'VO.'

37-1-7

3 7 - 7 < t

37 •0''.

4 2 - 7 i i

i 3S-07

i 35-71 I, _ i: 35-02 !i •1 35-59 ;

; «-si !| 33.43 |' 30-19 !

!103

I.<-ad E

Total

10-57

2'M'J

30-41

35-0'J

32-03

34-7J

3?-07

33-12

33-13

weu

39 -55

34-S1

36-63

Siniinarec:— Mi

In Fccc.-

«t • 02

* '

2^-K-

oft . 2 i

37-62

30-95

S 2 - J I 7

30-32

31-81

31-43

35-05

37 -7S

31-74

33-97

!ii?rcims•In Vri:ii

0-W

0-SJ '

1 • 2 J

1-07

1 - G S

1-75

1-73

1-31

1-T2

2-33

1-77

2-07

2-61

___________ —————————————__

ll'l M'TMlCUSSM OF LIAU C."

in i«f f.icls wlii-.-ii art.' pcniiifii'..The first of this KTks of experiments ispresented fairly fully, in order to demon-strate tlit- method of assembling the datafor study, after which corresponding partsof others of the scries arc* shown for com-parative purposes.Experimental Jlc'iiilf*

In Table 17, the early findings of theexperiment in winch subject M.U. wasunder obsenation for a little less than fiveyears, arc arranged to sho'.v the lead con-tent (if the fuod and beverages, and thatof the feet* and urine, us these have beencomposited for euch of a series of 25-day

AttNOKMAl. COMVTlCP.'.

up for each v.cels anil thin f"r i.u.: piot four \\et-ks). The primary ii.n^u.-this table is to present t!i(' sumin.i:;findings of the initial period In-foreadminUtniUoii of lead in solution, in j:position to the early months of tn-.- e\tmental ingtslion. Only two point- inassembled datii call 'for .tpcci.t! r-otnamely, the general trend toward ;•. ]grcssive increase in the urinary lea.l u::as the experiment continued, and tin. iof such increase in the fecal lead Out-,Hotli of these phenomena will ajipe.ir i,;strikingly later.

Table 18Lead Intake and Output of Normal Subject (M.U.I

During Oml Lead Administration

Successive Lead Lead Eliminated — Milligrams i Lead—?'.,.Periods Inptitcd * ——— - —————————— ——————— LUJ.I.I—' nr

of 12 \\>cks MUhgrain» Total • In Feces : In Urine Kctainc*! i— .

l*i ... ... 112-S1 101-4S ; 9S-321

ilnd ... ... ll$-74 105-9-. ! 103-74

lira ... ... 107-22 K>5-M 100-15

4th ... ... 11S-7& 111-07 ; 105-57

I*lh ... ... 110-1* 111-22 ; 104 -C6

Oih ... ... 110-22 : 121-59 . 114-ld

7th ... ... 109-44 ; t'3-41 ; 80-57

; 3-10 , -rll-3'.

! 5-21 •••• fr-2'«

5-3C -r 1-71

G-Cc'J «- 7 - 2 J

C-5G | - 1-^-1i >

7-44 — o-oT

G-si -lo-o;.Sih ... ... 125-40 , 114-80 112-47 : C-3CJ -i- 0 - M -

6th ... ... 117-11 ] 114-81 I 10S-97i ' !10th ... ... 105-48 ; t)3-8G > 01-22.! i

llth .'.. ... 107-57 : 100-19 i 102-23

12th ... ...- 114-24 , 102-00 1 34-03i

13th .... ../ lU-U 100-08 1 94-02i t '

TOTAL ... Ut*'42« | 1,398-19 1.316^12

5 -Si • - 2-3 ' '

7 -04 - - G - C 2 '

6-94 — i-c:8-03 -i-12-lS

' 0-66 i -i-12-4r,i

82-07 j 78-23

* Approximatlftv 23;90 Wfji, in drinking water, 372.32 mgs. In food tnd other beverage,and 1.082.10 mgi. tdmlnirttred to tohitton.

104 .

. of

( . . .th-.- i :p;ri-

v. a i , l .! pru-!«•-.'! 1'iitpi:1.

«

Til''-'t-lcrtiiLnit 'urj., t"the1 uclucre.'.lo id.\n-Vsruv.s (jcct.\veuV . I H I .

, .:! V .s ini'e.>t'.''l (i.'.iiy i ' i ' i ;i't;l.'ji'/;i 19:.:..ir/'d in t lr1 diet-1, luivc hccn einn-

f'-'i >ucccssive periods of 12 \vccks inl1^- J'1CiC' c'a*-1 demonstrate moretluin tho-ip in Tiihlc 17, t i iC ' uneven

:n'.-->Hy pro^rcssixc inere.isc in t l i y\ o;i t] i i i t of lead, an:! they cstuMiihcurroiu-o ut an irreiiul.uly proi.TC.wivo"' in the deficit in the total output ofii* u'Mi'tnred \vith (he tot.il in take . .i.':it'y. under those conditions, Kid;cunui!.»;iui: in the body of the Mil)-It i.' apparent, however, that thcr,^iMK-i in t l i L - citnrsc of this experimentthe ( n i t n i i t oi k:.ul from the bodyr - >n. . : i e tu iv . i i cn t to tlie intake;

tMi.-c v.c:-:- a^ci ilirc:- periods, as shown i1'.T..I.V, ;'. v.-! , , . - , t-v --put w,, s;.:iu..v:.:iK r f i i U r ti..iii the intake. V.'c shall f - x n i u i i n -these i r ro^ulLir i t ic . i it l i t t le Liter.

The f icts with reference to the soura >and quantit ies of ingested lend, the avenuesand the extent of the output, and the mas.-nitude of the deficit referred to abou-,during the entire period of the experimen-tal ndir.ii.istration of lend, are summarize.!ii: Tali!;- Ij. It may be noted here. f«rwhat it may be worth later, that the quan-t i t y of lead excreted in the urine duringthis p"riod W.T; practically equivalent tothat returned in the body of the subjectA rough, calculation will serve to show thatupproxKr.r.trly 70 miilitrrains of lead wereevcute;! in the urine during the perio:! nl

L-.:.Table J9

Lead Intake and Output of Normal Subject /M.R.)During Four-Year Period of Oral Administration of Lead

MilliramsPercent of

Total Inc-stio::

In d:inki::~ water

In fuod and bLVcru^cs ...

AJmiiustorcd in solution

SO-Od

-195-17

1,412-SO

1-5

23-3

73-2

TO'I.AL l . t 'T l -ST 100-0

- i - e :•12-1*

•12-4-'.

7S-93

Eliminated :

In feces ...

In urine ...

TOTAL

, Retained

1,739-31

113-77

1,853-05

110*07 '.\

83-2

5-S

94-0

7*8

105

_JJ^_

Tl.! ' «"! 1. \ t iOll!-M C'l I LM> U SM X

' A- .' ;v\ -4- • r- • • •'•*&"*''J- '

i-a*1*.''

*%*'•*ViV.

i i t i i i f i i i n .! absorption more than would h,t\v1'.-. ii i'\;-ri U.: i::xh :• iv-fin ' < .mditi:-:-1-.This cakulatinu is made !.y multiplying theCross urinaiy volume during this period,by the riK'iin concentration of lead in thuurine of tins subject before le.Kl was admin-j*tcrcd, and subtracting this product fromthe total output of luul in the urine. Dis-rcgardin:: the indeterminable quantity thuti i iuy have occurred in the feecs as a tmeT-xcretion, \vhich may have been of aboutthe same magnitude us that excreted in theurine, this quantity i'70 mg.). when addedto that retained in the tissues, adds up toISO milligrams that may credibly IT takento have "been the minimum quantity oflead actually absorbed from the alimentarytract iti the course of this experiment,roughly 13 per cent of th.it administered.

or somewhi't k-« tl,..:i 10 per cc. , , of I:.-.-. .

At this puiiii in tir. cic.-'^ip'jtii, i.', i(••:pi.riincttt il mijiht serve the pu rp - . - u*•brevity and, al the same timi, con t r i l -itiformatton lor comparison, if wv vc;\-introduce data enrrfspontlinj; tn tlius-.-Table l^J, but derived from another i\j;'.ment, in which subject E.H, ini:c>tetl tmilligrams of It-ad per day, in uc ld i t i ' ; ; .that in his did, over the period of V:;what less than two years (u'Sl dayj-i. Texperiment was carried out in 'preii-,the same manner as that of the fir:*t e\j 'ment and in coneurrenee with the l.ittc: •;.of it. The corresponding data art- siiii .iiiized in Table 20, in which it can In- sthat approximnU-iy twice tin- daily c1n»tlead per day resulted in the nccunmVit ;

Table 20Lead Intake and Output of Normal Subject <E.B.)

During Two-Year Period of Oral Administration of Lend

i'er cent 01Total

In drinking water

In food and bevKajre.*...

Administered in solution

•• .-. MM: ,. ,- ..-,: M 1' i! ft KCLtl . l ,'. Kl HOC

. i; v.y y/iK- t:.:;•;:: t • ' • , ' •« , ( r{

:. :: ;..-. e .sea.•:.f „:.•:!;. cV'-c- of

4--2-

M«MHiVI&> * i j2 < 6

TIV£

rtMKSlie i: i;

tfi SUCCESS. '.'£

— • —— .̂ fe .̂̂ ^B. — — — .. — -;,* '. V •» V -i> > ' ' '* • •

• i ' i i . . i i i i irf.»€l C^S^rs" " » 29

-1; « "'•' S3 ' 32

i

..*y, ^i^Mi t i < i i i

34 36 33

f':ir. 1. Cfftitttiic rn>rcu"*'.'i n f-t i' <- i,ii~."titi<^ nf lead ttikcn in font'. Lrifrc.sct iini! initftfn''•"'•'! ' 'i i f / i nifi'"' ';' t'fi-'< <' i.' " ' i trvi ' .r f'cri'ffj (»/ 28 (My*1, ftf.c/ ('li1 c;ii«i.'fi!iV ••(•?ti«J(K(f(. . ' i'l (''(" Hfmc f / i . f t /'.tT- . -"MM c,'; in l/i

..1 ti!C

f K idI . . i t n •: '1'hc- the, i r n \ i d;.c,tidi . u.is

l i m m t s -

of anprovim.itt-ly the same ( | i i a n t j t >iii the Ixi.ly ol sulijcct E.li. in it ime . Aeaiti. the quant i ty cxcre t t ,urine durir.i: tlic admimstrati 'Twas approNiin.itely the same .11 !taincd in tlie body of the subie-.tjnantity of lead absorbed dunperiod of the administration of le.uiat by tin1 same procedure as th.nt i;.in the case of subject M.K. a!:rvcertainly not It'SS than 165 rr.,iwhich is iil.out 13 per cent of th.it .»tcrcd. and almost 12 per cent of t ' ic tx.ilquantity ingested. (The total q-..intityausorbed may well have been of the orderof 200 milligrams, or 15 and U 5 -,i?r cent.respectively] of the administered le.id, andthe total quantity of ingested le.id i

A graphic view of the gross quantitativerelationships between the incesterl lead(food, beA-crages, and that adintmstrred1.that in the feces. and that in tho urine,during 39 of. the 32 periods (each of 25days) over which lead was administered*o subject M.R., is shown in Figure 1 Cer-tain trends are clearly visible—the generalcourse of the increase' in the urinary output« lead, the essentially parallel vari.ibility

of the total infako and output of loadduring the tots! period portrayed, and thrcomparative constancy and yet tiii- slicht-ness of the discrepancy between tin- intake;uid output, as referred to previously i:;Table 19.

A further series of charts have beendrawn up to revf-ul certain simple but sic-nificnnt facts. Thus in Ficure 2. the outputof lead in the feces may Le seen to have ,\well-defined relationship to tlic lead in-gested (since the amount administered wasthe same each day, the variability herederives from that of the food); it also birea. direct relationship to the regularity ofthe emptying of the alimentary tract. Inassembling the analytical results on thelead in the food and feces, for scanning asthey were obtained, it could be noted thatthe failure of the subject to defecate duringany 24-hour period resulted in a discrep"ancy between intake and output which wasnever fully counteracted subsequently:evidently, a greater degree of absorptionof lead occurred when the retention of thecontents ot the alimentary tract was pro-longed. In this manner, this factor came tolight.)

MtT'StOLKS! Or U'..\M i. M \l COST.; f t-.v •

II< I? 1!

—I*»

; 5«11 ,« » » t

S——M

.v, . . .--V -y —— / — ,-.. — L.' -.-\.

v^~-v^--^s^__ew A ^ y\ A.

N/ V7 Vr\^-

i; M tt :;»•«! . I» .» i ' •!• tSl

Ti?. 2. 7"iif rrlctipii between ('if fo?a/ IM^ ou.'ivif in t/ic /rcc* i«Micr»t«*( 'I'M1*.- of(VfmCfftfrf pi'inft . t/ic fpfrtl iiJcl;C (if Jf(74'i in Icxni. I'fi'CffifCi mtj in Joditi'^i <r,ir:;.';\" .".̂ --io* rc<*irtrrf£d iifiuti;, oi\d t/ic irrf^ii?(ifi(y ifas: (*' the fcrcl ewntfji-wt {f-.*!ifrmr>-f jcr : f i .(j.v represented for tttch of 51 pCTiC'd; of 2S d«'/*, (/urine rt fir;>.'(.»-ii;f(( l i f r t<irf n: t.'::."'i 1

milligram of lead was ingested (u'irii ricalj* drtiiy. Subject M.fl.

Certain f.icts wilh respect to the leadcontent of thi- urine and nlood during theentire period in which lead was adminis-tered, arc shown in Figure 3. The meandaily output of lead in the urine, the meandaily concentration of •> lead in the urine,and the average concentration of lead in theblood, for each 28-day period, are plotted.A point of outstanding importance is thegeneral upward slope of the three curves.There are frequent peaks and valleys ineach ot them, as well as certain less fre-quent downward swings in the two repre-sentations of the urinary lead (which willbe remarked upon later), but despite thefrequent or infrequent recessions theireventual course mounts to progessivelyhiuher values. There is no evidence of theachievement of an equilibrium with theexperimental conditions.

A further point of importance is thesomewhat lesser rate of increase (moregradual slope of curve) in the concentrationin the blood, as compared with that in theurine. This difference is not as evident at aglance, as it fs when the sharp and frequentdeviations of the curves are ironed out in

fitted (straight line) curves. .15 illustratedin the case of the urine in I ' iuut? 4 lu.low.(The lag on the part of the Ki»'»d i' themore pronounced, the higher ilv- i itc ofabsorption from the ahmei.'.,u\ tract, i.e..the larger the dose of soluble k.v.l intri-stoddailv.l This phenomenon wmil:! <rvm r.otto be especially remarkable vl .cn onereckons with the fact that the cunceiitr.ittqnof lead in the blood of the M'<r:v . . . l indivi-dual is approximately 10 liu;^ tit.;*. IM theurine. Indeed its ummi.il fe.ii,.re is notthat this discrepancy occurs h;U tint it isnot considerably greater, fcir virli wouldcertainly be the case b-.it for the tMpicityof the erythrocytcs to take up Ir.id andthus retard somewhat iti passage from theblood Stream into both the ti<si:es .nul theurine. As we shall see later, the usual limi-tation of the rate of the urin.trv excretionof lead does not depend or, a normalincapacity of the renal apparatus t - excretelead beyond a certain low le\e! Imt uponthe limited availability of lead for excre-tion. Thus when a sufficient quantity oflead il available in the body, the urinaryexcretion of lead may be augmented thirty-

10S

^^^^^^^^^^Si^^M^M^^iJ.-;•-:'. IVI Ml. & II! ROUSR1 A

....:: —I

b! ••;'. i* tl"1

: '<.':.•: rate of•.".• tr;.:'.. i.e..

or.e

.= ;:-.' :-?.iv.:-c is not...._.; :...- .'.i-U jt is•*:. :"•; >::ch would' :: :"•:' the c.v.iaciK

• -iV- •-.:? l*ad and:-.» r.,?.M:f from the. ±'t r.55:.'.H And the.

.* ---.:.r\- excretion.:•:-:. ::.' a normalV-'-ituj to excrete;:-.v :*-.-*:. b-.it upon

:: '.ai f:r excre-.:r.::fL; c'jsntity of

-s b'.fv. tr.-1 urinary

T.MI. 1; ;*« H1"'

Ft*. 3- Mean ttui'y output t-t katl i'i urine, at:t! mean rfflify concent ration of lead in urinecm! b-^od, in c-.ich ;>erto(.' o* 25 days, during a prptonprr; prriorf in ir'iirh 1 mti/tgram of

lead, in jo/[.-.'fc>.'i. IHAT ingcttai, daily, with meals. Subject W.fl.

fold or e\ rn more. At such a time the con-centration in the blood is likely to l>eincreased only eight or tenfold. On theother hand, under circumstances associatedwith abnormal absorption of lead, and alsowith an impairment of the renal excretionof lead—a situation which occurs onlyrarely—the concentration of lead in theblood nutv be elevated by as much astwenty fold.

In Figure 4, the total output of lead inthe urine, and the total volume of the urine,for each 28-day segment of the total periodinvolved in the experimental administrationof lead, are plotted in parallel. By thismeans, one is enabled to see that thevolume of the urine it an important factorin the urinary output of lead, and also that(in Cincinnati) mere is. a well-definedseasonal factor which influences the outputof water and the output of lead in an essen-tially parallel manner. Many (but not all)pf the minor irregularities In the output oflead over the entire experimental periodappear to be explainable on this basis, whilethe low points separated from each other by

larger, serrated, upward loops, coincidewith tht peaks of summer heat, approxi-mately a year apart. And yet, despite allof these deflections, the main course of the•curve is steadily upward. Whether thiscurve is best fitted by a straight line maybe questioned, but such a question at thispoint in our discussion may be dismissedrts of little importance. The importantpoint is .the fact that there is no evidencehere to suggest that the upward trend willdiminish with further time. For aught onemay suspect to the contrary, this samecourse might have continued upwardthrough the remaining lifetime of the in-dividual, so long as the experimental condi-tions were maintained, and, as we shall seclater, this, in all likelihood, would haveresulted disastrously for this experimentalsubject in somewhat more than three addi-tional years. [The special experimentalconditions represented in the latter part ofthe curves by the arrows under the heading"induced dietary changes," will not bedealt with here beyond the brief commentthat they represent a series of crucial tests.

J?%SaME •?£

Tl iL M F T x B O L I i M Or LtAL> VNOCIt Al"<OHV.M. CQSOit lONi

I.

•« *» t;

Fti*. -I. TI.e relation l>c(u<vinrtnc. it:

n l>c(u<vi f f i c crow p»f;mf o/ leaf in tirino and the crins volume c** t'ncji-"t"(/; t<f is (/<j;<t. (tntiiis n prolonged pvri.)rf in H'/iic'i 1 ?ni//t;:r<m. o*

.'. if; ic> ' t i f iO' i , udi itcrt tod ditilij. uit'n mfah. • Sub/ccf .M.It.

(if certain dietary or therapeutic methodsof altering the retention of lead in thebody, which can be seen to have influencedthe output (and intake t of water, and thusonly indirectly and insitinifieaiitly, the out-put of lead. These were, in sequence, (a) theadministration of milk in large volume, (b)the administration of larcje doses of ascorbic-acid, (o deprivation of dietary calcium, {dithe deprivation of both dietary calcium andphosphate, and (e) the administration ofexcess of phosphate, and (g^ the admmtstra-exccss of calcium, (f) the'administration oftion of excess of calcium and phosphate,one administered in the morning, the otherin the evening, to diminish their directinteraction. Each of these procedures wascontinued for 28 days, after which the sub*ject resumed his usual regimen for 2S days,with the-exception of procedures (e) and(d), the latter of which followed imme-diately in the wake of the former]

In view of the apparent physiologicaland practical importance of the* influenceof the urinary volume upon the output of

this

lead from the body, and in rococniri'iii ofthe dearth of quantitative inform.it ioii .derived from controlled tonditto:-' ofexperimentation, on this matter, the n-.iror-t unity to carry out certain detailed o!i>tions of this type, in the course <*£experiment, was too tempt in;.: to p.i« by.Since also there was little or no mfonvuti»:ias to diurnal variations in the eoiK'Ci.tr.itioiiof lead in the blood, under fairly constantbut abnormal conditions with respeet to theabsorption of lead, the blood and tlu- u r ineof subject M.R. were sampled at intervalsof two hours throughout a period of 24hours on each of three different occasionsduring the period of administration of lea<j.The first observations were made five andone-half months after the initiation of theexperimental ingwtion of lead, the second.19 months later, and the third. 10 monthsafter the second. No additional experi-mental variable was introduced into thefirst series of observations, but in order stillfurther to intensify the variability of thethroughput of water, the second and third

110

K 11

:'fr:i'!-!:r..-.V

ofj : i .of

u- cviirv df t i i i iJViir: t ' p.iv I')'.nr t . - i : i f i n n . L t i i mtht c.'!i;vntr.ituw

-c-t M (lie

•• -i!iv'; .it intcn.i!.-;i iv.-iod -of 24

'iV^Yrat^'of lead.en- nude five and,c i i . i t iaMon of thef Ic.tii. the second-

third. 10 monthsadditional expert-troJucrd into the>. but i:. order stillvariability of the

• sec-'od and third

C[,.s of f.liscrvaH.-im \vcrc c.irrie-*! nut ii?j,-in-r»- clilutioM-concc-ntration U-s'.s, the-jV-ijfcci f:r.it boint; given ;m excess of watern?"tl.c- start of tlie obsen-ations, «incl tlicnbein? deprivei. of water until the regimenof Mmpti»tr bad licen complete;!. Theresults nrc plotted in Figure 5.

A. KLH0C [Mi,. [«-,

It \vi!! !"• nnf'J tn it t ' ^ e C'H;-;-fTitrat:3iiof lead in tlio )>loo;t varied only insignifi-cantly only one result, on 9lli January.ly-10, ranged above the upper limit 6tanalytical variability) during any one of the.24-hour periods, but that tlic level of con-centration increased step by step in the

I""

< i i i

I A M J.IM? • * I.' *•»•;* S .IMIT I M E i s H C J I S

J'iz 5. Dittrnui nm'flfriUM i.-. f/if c.'ncculratijn of lead in the urine and blft>id (lowertceti»ti* . in nluHjn t<j taw,-if r/r/f, trt>t>cr ic'cfinii* end induced (centre and right uppert>:ct>i>m itriiiiji.t in thf i;>!nm-' c1' ('<•" ttrit.r. tttirin; three 24-htmr period* in the course

of a ;i'.»/(rttpfrf ;•-. •/•:„•;.' o; r.v;>vrime'iif.;J iu^ri.'iou o; /«,•«'. Suhjtct M.R.

! /\

/tMJICT I /"

4 * I* I* tt It, *t «• • *« 44 |t«ic, it-wt n*«n

Fte. 6. TA0 cn»iM^tfft;e difference between the gross intake of lead in food, beveragesand that invested in solution, ftitt/ tlic grvss output in the ftces and urine, in successivejmrtod* of 25 days, diirine jmiteiiS&l period* of experimental insertion of lead. Subject A/.R.(1 mjr. per day in solution) end tultject E.B. (2 mf. per day in solution). Each, pointrepresent t the total quantity of lead retained in the body of one of the subjects at the

corrctpttndirig period of the experimental sequence,111

THE METABOLISM OF LE*D UNDtft ABNORMAL COSUUlONi Ueucul K I P H A it.

successive periods. The urinary concentra-tion of lead, on the contrary, varied widelywithin each period,, in inverse relation tothe urinary volume. The extreme expres-sion of this variability occurred when, onthe same day (3rd March, 1939J, while theconcentration of lead in the blood remainedessentially constant at 0.033 ing. per ICOgrams, the concentration of lead in theurine ranged from 0.05 to 0.21 mg. per litre,at the opposite poles of the urinary volume.This high degree of variability should benoted and remembered in relation to thefrequency with which attempts are madeto establish the general level or rate of thecurrent absorption of lead by an individual,through the* analysis ot a sample of urine ofsmall volume.

Next in Figure 6, is another aspect of theabnormal metabolism of le.ul, as revealedin the two experiments in which subjectsM.H. and E,E. ingested 1.00 and 2.00 millirgrams of lead daily, respectively, in addi-tion to that in their respective diets. Thecumulative retention of lend i.the grossdifference between intake and output in thebodies of these subjects) is plotted on amonth by mouth (2S cLyj basis, the result-ant two curves being practically tie sameexcept for their slopes and tlvcir representa-tion iii time. That is, subject E,B, reachedpractically the same end-point as that ofsubject M.R. in about half the time, asshown previously in the end results,Tables 19 and 20. It may be noted thatthe points on these curves could hardly befitted by any other than straight lines, andthat there is no suggestion o£ a terminallevelling oft'. There arc e\ idcnce* in bothcurves, however, of a teem rent levellingand downward trend, in the form of fournotches in the four-year curve (M.R.) andtwo in the two-year cur\c lE.B.), theseoccurring at the same time of year in bothinstances, namely, in the summer season.

The meaning of Figure 0. in its simplestterms, is clear, but ti« .very simplicity ofthe {acts may be deceptive, and perhapssome further'consideration should be givento them. These two experimental sub-jects, as well as n third (subject I.F.) whoIngested three milligrams of lead, as a dis-solved salt, every day for four months,suffered no deviation from a state of well-

being during thysc experiments, and, there-fore, it micht be concluded th.it these dailvdosages of lead have been proved, thereby,to be harmless. So they were, for tl'.:period of time represented in the experi-ments. If, however, there is a point atwhich the accumulation of lead in the bodvbecomes, of itself, dangerous (evidence willappear, subsequently, to show that tins isthe case), we must view these experimentsin a different light. Unless these subject*,if continued indefinitely under their respec-tive conditions of lead intake, should, a:some time, achieve an equilibrium wherebythe intake and output of lead would ccrneivito balance, they might well be threatenedwith lead intoxication at sorm* time. It isimportant to recognise, therefore, that noevidence of an approach to such an equili-brium is offered by the results oi tnc!>cexperiments. \Vc shall return to thismatter at a later and more appropriatepoint.

As to the seasonal variation in the le^dmetabolism of subjects M.U. and £.15., nosatisfactory interpretation can be given. Itis pertinent, however, to call attention tothe fact that the excretion of lead in thesweat of these subjects, to whatever extentit may have occurred, is not accounted forin these curves or in any other representa-tions of our data. If such data were avail-able for inclusion, they would further in-crease the loss of lead from the body, andwould increase the negative metabolicbalance, thus deepening the notches in thecurves of Figure 6. It is evident, then, thatthere was a greater excretion or a lesserabsorption of lead by these subjects in thesummertime, liut the reason for this pheno-menon is a matter for specuUttloti. Was ittemperature per AC, or sunshine, or thegreater seasonal recreational exertion ofyoung persons, or the crcnter use of freshvegetables and fruit during the summermonths, or was it some more subtle changein the general metabolism of the body?

A further experimental variable, that ofdosage, remains to be examined for its com-parative effects upon the patterns ofresponse of the several subjects. Theseeffects can be illustrated in a few chartsand comprehended promptly and withlittle farmer explanation. It may he of

112.

U.-iM'i n I.P.H. « H.

riments, and. tlwic-U-cl that these dailyon proved, thereby,hey were, for trietied in the expert-here i> a point atof lead in the body

.-rous 'evidence will-j show that this is. these experiments.kss these subjects,tmcler tiieir respec-intake, should, at

ji i i l ibri ' tm wherein'•i lead would come: well be threatened-: some timo. It is

U'herefore. t lmt noto such an equili-

* results of these'I return to this.nore appropriate

• riation in the leadM.R. and E.ll., no:\ can bo given. It

to call attention totion of lead in tlisto whatever extent

s not iiccounte'.l fory other I'L'inv.-viita-;h data were a\\-.il-would fu r the r in-

:':o:n the b-xh-, and

:rtf hotel i •. < in ti'.eevident, then, thatrerion fir a lrs*er:*«• subjects in tiic

..;:•:• for this i)!-i*no-

j'.i-i'jhmr. • or the.ti.'-r.Al exertion of:r:.^te-r use of fresh'.•..:::'.z the summer••.:::• subtle change•::: cf tiie body?:.-: v.iriable. that of:i:r.;ntd for i Is com-

the patterns oft! !-.:lv>cts. Thesef,: in a few chartsr::r.r.:ly and with•-. "it may be of

H 1 -r .11. * H.I KOttCKT A. KEHOI [Mtv. ll'l

interest to mention the fact tint the dosageof 0.3 nig. of lead per d.iy, taken by subjectS.\V. tin addition to that in his diet), wasselected by means of a rough calculation, inthe belief that it might result in an , mountof alimentary absorption equivalent to thatbeing absorbed in the respiratory tract.This subject had just completed a periodof 13 - lunar months of observation undernormal (control) conditions, during whichhis output in the feces and urine had ex-ceeded his intake in food and beverages byS.5S milligrams. This excess was regardedas having been absorbed from the atmo-sphere in the respiratory tract. If ourestimate of the appropriate dosage for usein this experiment had turned uut to becorrect, the intake and output of lead,charted in the usual manner, would havebeen in balance, and the actual amount ofthe respiratory absorption would' have beenindicated by this indirect procedure. Thisturned out not to be the case, but it eventu-ated that this was the least dose which,when ingested, would be absorbed to suchan extent a.» to yield incontrovertible evi-dence thereof within a few months. Thisfact and curtain others are shown in a seriesof charts.

Figure 7 portrays the mean daily a'imen-t.iry intake and output of lead' by sub-ject S.W., during the 11.5 lunar months ofthe control period, and for the 17 monthsthereafter, during 15 of which, the dose of0.3 mg. of lead was ingested daily. Thischart is introduced merely to demonstrateagain, for emphasis, the familiar relation-ship of the alimentary output of lead to thealimentary intake, over the entire period ofthe observations. The extent and theabruptness of the changes associated withthe initiation and the termination of theperiod of experimental ingestion of leadare apparent.

The situation is different, however, whenevidence is sought of the absorption of leadfrom the alimentary tract, under the con-ditions of this experiment, l>y examiningthe data as they are set down .graphicallyin Tables S and 9. The two "lowermostcurves of Fiuure S represent the meanquantities of lead excreted per day in theurine by subject S.\V. during each 25-dayperiod of this entire experiment (the perirHof ingestion being superimposed, for pur-poses of comparison, upon the controlperiod). In three of the periods of 25 cl. tysduring the experimental ingestion of Ic.vJ,

Fie. 7- The Rron Intake of kad in food and leverage* and the grost output of lead tn thefcces, for eadt period of 23 day* in sequence, are plotted at indicated, in the initial andfinal sections. The lead taken tn solution along with ('iff food, is added to that in the food,in each successive pertott of 25 day*, during, the total period in which 0.-3 mg. of Ic-sd

inn ingested <i4/y. Subject S.U'.

THE MtTABOLISM OF L£AO LNDEK AftSG*M,\l.

the output of lead in the urine w.is signifi-cantly greater than it had been in thecorresponding part of the control period,and, during the latter part of the period ofingestion, the general trend of the urinaryoutput of lead appeared more and more todeviate from strictly normal levels. Mostof the time, however, during the period ofingestion, the difference between the twocurves may be seen to have been negligible.The over-all difference is barely ofstatistic-.il significance. The other curvesin Figure 8, with the exception ofthat of subject I.F. (3 mg. of leadper day), whose period oT ingestionwas too* brief to bring out the main orultimate slope of this curve, reveal theirown trends and diverge from each otherand from the b.iseline in a generally de-finitive manner. These elongated curvesare plotted on approximately the sameseasonal basis, and although there is somedegree of conflict in their seasonal trends.

5i:»p'(" inspection is a s^Kicifnt mean* nfdilierentiatin? them in relation t-i Uie d.uiydosage of ingested lead.

Fijfure 9 provides a comparison of curves\Miicli differ in their cuitslriiction fromthose in Figure' 8, only in that each .pointrepresents the mean concentration, inati-ailof the mean quantity, of lend in a series of2S samples of urine each nf which wasone clay's output, these being plotted intemporal sequence. The visual compari-sons are facilitated by the inclusion of ,\straight line representing a mathematicallyderived slope for each "curve i except thatrepresenting the control period of subjectS.W.). There was a barely significantincrease in the concentration ot lead in tin-urine of subject S.W. during tin- period ofisii-estion. The other curves lu-.ir ninththe same relation to each other us those inFigure S. In Figure S). however, the inade-quacy ot" the curve ''subject I,IV which Uintended to represent UK- ivspoim1 to the

TiMC tH SUCCCHIVC HHC9S Cf 21 0*r?

8. T^he mean daily ouf;)»t of lead in the urine of cadi subject M idrnti«cJ. i;.icrcnfi:? pcrtodjf Of 2S days, Including the preliminary (control or base-line^ r/rf«rt n*

titbiccts Af.fi. (1 mfi. ttcrdaV), E.B. (2 mg. per duy\ and I.F. (-3 me. per rf««V Swl'jft'f S.W.is represented by two curves, one broken, portraying the period duriiif which mt tctitl t fo-taken with meats, and the fthtt, continuous, covering the period durinc which he ingested0.3 ntg. of lead per day. The prtnts plotted in thf case of subject .V.fi. represent on'.y Cn-

' first 23 of 52 periods, u/tic/i could be compared tilth thvM of subject E.B.114

R I l> II 4Journ.i R i MI * ROBKRT A KEHO£

f r i & i c i i t me.iiii ( ,fation to the d.iiiy

iparison of curvesomtructioii fromn that each pointentration, insteadlead in it series of:h of which wasbeing plotted in

•* visual compari-he inclusion of ,\a mathematicallyurve (except thatporind of subjectbarely significant'ion of lead in the

ng the pi-nod ofrrves bear muchcither fl' those invever. the in?cle-.•t I.K.t which isresponse to tlit

:: i- :: i> I*

(. ini.'. Siibftcl S.U'.

;icJi »w k**»f ww(ricrrtrrf

FU. 9.

t i « t * ' i i -o 11 : ; • * • » »«TIME i-'i SUCCESS;.* «»•::$ c^ 21 CAT)

TJ'f mcati rfdi/;/ *tiMTi.''ifmfi"H n/ /t't.'if i'i t/if i ;r if i<- c/

Fi»nrt' b.

i -t i: t t: ii t*

f.'Ctf S.U".. .V./i.» K.W.,

in. of c. iytor

iplus

r E.B.

iugcstion nfthat itt tin- fthe Iw.'i iuljacvut au;l livnv niolmr^fJcurves ti-ml tn lc-\cl oH Snii iful i . i t . i l cv r .iniiiiti.il sh.trp rise, this um.1. Si-t-mii !',;!>•, por-tr.vys ( - i i l y tl .e i ; i i t i . i l sKtpc. OIK- wouldliU- t" kunw what would luvo lu-cn it-ffu ture eour.se li.id tl i t1 e\porinu-nt Ik-enpro!.»ny;ul.

The (iccnrrencc ' nr nnn iccurivjici- olsignificant changes in th;- ci i i ict n tr . i t ion ofl('ud in the lilood u\ the tour suhjccUduihiy those experiment* is shown graphi-cally in. the CUIACS of Tiijure 10. 'I'lit: two\vli:ch represent the two periods ol theexperiment imolv ing subject b.\V. cannotbe differentiated, nor could these two setsof data he differentiated bv statisticalmeans. It is possible that tlioc curveswould have diverged significantly, it thissubject had adhered to the same experi-mental regimen for n longer period of time.This is not certain, however, and the factjs clear that the absorption of lead at thisjevel of oral dosage is so minute as to bebarely demonstrated only by a slightincrease in the rate of the urinary excretionof lead, without the confirming evidence

i-f un i:icp.v.^' in the coritviitiv.Uou of leadin the- bird'.!.

The c-rnvs which s!n-w increases I'M theloncci i t r . t tMn of U';ul in tl'n? bi-i-nl , in .i-.-'..ei.ttion '.vith v.iryin:,; rates ul ab'.orpli'ri ,>c.h-.id. slope much in.'re iitntly upward fi-":uthe lia-ii.- line tii.tn do th-in1 indicative of th-.tale* of the ur inary excretion of load -F i^ .9 . and they li-ml to d i i tVre t i t i . i te t la-in>\-lu->(Yum each o t h f - r to a Its-or < \tcnt ar/.i in >;•t^railn.illy t l iau do the '.Mrn.sp mdini; n r i n -a:y slojit'S. On the o t iu r h.iiii!, it t . i l l n u ^tluit e\ery deuiunstr.ib!-.' ciK.njrc in theblood i^ ni'.'i-c sipiifiCMiit , in I (.THIS of theilt'iiree of absorption of li-.id which inducedit, than is a comparable depve of cluinucin tlie urinary outpnt nr Coucentiation otlead.

A pasiiiii; reference was mude, .it t!iebegimuuj; of this discussion of the meta-bolism oi lead under abnormal conditions,to means of hastening the elimination oflead from the body—"deleadinq", as thishas often been spoken of. The accom-plishment (if this purpose has been apersistent goal of medical therapy, andmany remedies, among which were potas-sium iodide in un earlier period, ammonium

113

Mif. 1M1I THE METABOLISM Of LEAD VNUEK ABNORMAL CONDITIONS F. f PH \ H.

I t • » » » • » « " « . » • i t 4TIME IN 3USCCSWC PtmOOI Of 21 t*YS

it 19 r i: ti

Fig. 10. The tntan concentration t-f kiiil in the biot>d of subject? S.U"., M.R.. E.L*../T., plotted for cyrnporatk e jiiir/iojf r. ;:.r rri figure 11> unt/ 9,

chloride more recently for a time, andsodium citrate still more recently and ondifferent theoretical grounds. None ofthese agents is of any pr.ictic.il value inspeeding the clinuiiiition of lead from thehydv, (Whether they may yield thtMpvu-lic Vent-fit otherwise, is another matter.)An obstacle to the clarification of this andcertain other questions of clinical andlegal medicine, lus been the almost utterluck of precise information concerning themanner and the proportional extent,"and,more iiartitiiUrly, the rate and duration, ofthe elimination of lead from the body,following varying periods of abnormalabsorption. Every physician has known,or considers that ho know*, about thecunvilative characteristics of lead, but few-have concerned themselves lo know any-thing definite about the eventual outcomeof the ordinary processes of elimination.It is almost as though, in general medicalbelief, lead Accumulates in the body in theabsolute sense and without expectation ofa reversal «f the process, except throughthe intervention of therapy or intercurrentdisease. It would be an astonishingphysiological phenomenon if this were true,btit, as has been known for some time, it ifnot. Some of the facts have been disclosedby prolonged observations of the rate and

extent of the excretion of lead liy p.itir;.-or industrial employees who had U-::r.i-tutcd their occupational exposure1 tu I,-.; •temporarily or permanently 00'. Tl.eexperiments described herein (!tit:iJ..V. :' k-matter still farther, howt-v-.-r. hcui'i-.- '[the completeness and thv inuntu . i r . ' . rcharacter of the information wl.iv'a t inysupply on all aspects of the matter.

In addition to the fact that, af ter :' •termination of u period i»l ;ib;i^::...labsorption, a variably prolonged per: > ; :•:elimination of the aecuimibtH UMU n.- : •;—that is, an excess of output over i;.:,.-. --there is ulso a variation in ihc r.uc <.•: :;.;*loss, from one individual to ari.'itiicr, d- \^"i,-dent upon, (a) the amount ol Ir.sJ \vhi ' iiaccnnuihUed durin;; the period of i.hnonr..:!absorption, and also (h upon the K -lUtiiof time involved in the acctimnl.it .eprocess. These features of the eliminat: nof absorbed and retained lead are i"u>-tratetl, in part, in Figure 11. (n which arerepresented graphically the cumulativeretention of lead by each of this series ofexperimental subjects, during a period ofdaily experimental incest ion of a knownquantity of lead, and the accumulative !<>*$of lean during a period following thetermination of the experimental ingest ionof lead. Figure 11 also includes the

lie

U«,I.-!HI ft I Pit a S H ! ROBERT A. KEHOE IMJV. )**:

cnph-c representation of the correspondingbehaviour of two subjects who ingestedonly such lead as was contained in- theirfood and beverages,

The Icuend of Figure 11 provides theadditional information required to clarifycertain of the details of the manner ofrepresentation employed, but some com-ment may be required to bring out themore important relationships. First, itslunil'.l be noted that it contains a familyof ivLited and similar curves. The twosubj-.ct* represented in the two lowermost;md substantial ly identical curves, elimi-nated more lead in tl.it»ir u r ine and i'cces.

\vhich lead accumulated in the bodies ofthese subjects are indicated by the primaryslopes or the respective curves, whicn\-aried directly with the quantities ci: leadingested daily. The actual quantitiesaccumulated varied correspondingly, beingrepresented, in the intermediate and finalperiods, by the points on the curves.Despite the fact that two of the curvesithose of subjects M.R. and E.B.) tendedto cnfnciJc in their early courses (duringthe first i months of each), the metabolicbehaviour of the individuals was clearlydifferentiated otherwise, according to(1 us a go.

;.. /:;;,

f Ic.id by p.-rti.-:'.:';<whit 11.id tern1.!-exposure to Kul

iculiy i JO . The•iviii el'iekLU- the.ever, bcc.i'ssc of

llie i[nau{it . i t ivcation v.Ii ich t'u-ythe matter.jt thai, i i f t c r ti.eid nt ;;!>nnnr,;.I•loni:'-,]'pi'rio:i ofatf.l If.ui eiM'.t'Slut over iniak'.1—

the rale of thislt> another, ilcncn-• k ul Ir.u! which

.id t.J abnormalupon tho !ciii;lh

:he accumulative(.if the elimination•d lead are illus-

11, in which arethe cumulative

i of this series ofirinff a period oftion of a knownaccumulative loss•d following theimental ingest ionso includes the

7 ic. 11. 7'»V citnniti.iiir (/••• '<•.•,•• -• •' ' .<vt f.'v p.-ctr alimentary intake of lc:;ut and the:•. ,- '? en,'/"'' i-f ?<''.'(,' in f.-'ir '•.'.•( : . '.' ; . • • • i1. i . inrff "•:;•,; jn-riods of 2S t'«yr. ytrr thff parted*if tltitc intlit'iiti'il. Ti'.c tnf' '• -i.. ••• rr , . r i o i r..-;>rff4.'nf f/.ff tiCffflfitc b.ihiifc ct **u*crrc.'fi': tntiici'tt S.H . c.'K/ //•'., < - • ; : • ' • "•: ' " . •f-f- i i t ' ' fOfli7if:.ii!.f. T/ip Mptt'cnf slopes nf the/.•rir (•;/»,); r f/ 'f 6*:^' /i';iC r. ' jfn'M •.' •• -u NI''.'.P( i;y:cc;rr/. f/u' rf/dfrre r..fi't o/ CttfKf.'i'i.'ct.'Ofi,

/F., ri'.irinS the i,Cfi.<(!\ in:!1,<::,-.! ;•; n •' .. *i r / ' i y i". jetted, ri Mfufiofi , fiV;ify 03, 1. 2. <•':;.':3 »!,'., rcvj'rc(;ivf:/, o/ /f.?.-/ / / .* «.'"i-.ifsr;/ j.V;'ft o,* f/ic f/irec ctirtt'f identified a.t

ft;1*/. foHowitiK the ti-rtnin-.'ticii > • f ' i< r rr;,"f'rtr rfijds of experimental inscttivn of lead.uliilc the rcid'i'i i'K/ifi.d? (';r < • / ' • - • • ' • • • * ' ' • ' '!"• "bed titut arrumulittfd ktid remaining within

the i'ji/.^t c/ .''-c rcTf>i'<fi(.v subjects.

month by month, than they ingested u i t htheir food and beverages. As indicated '"the first lecture, this is readily explainedIjy the lack of any representation in theanalytical data of the lead inhaled andabsorbed from the atmosphere. The oiliercurves, which", from below upward, repre-sent the behaviour of subjects S.U'. M.n..E.B.. and I.F., who. in addition to the lendin their diets, ingested 0.3, 1, 2 and 3 mg.of lead per day, respectively, show thateach of tliese subjects ingested more leadthan he eliminated. The relative rates at

\Mien the intake and output of leadof the three subjects were followed afterthe termination of tire experimental inge's-tiim of lead, the situation was reversed andthe lead that had been accumulating nowdiminished. The eliminativc process, ineach instance (after a brief period ofrelatively rapid decrease in two of thethree), proceeded at rates which wereappreciably lower than the respective ratesor accumulation, and appeared to van-inversely, among the three, with the lengthof time over which the accumulation had

117

Mav. 1HII THE METABOLISM OF LEAU VNUtR ABNORMAL CONDITION* Uaarn..! H I r H J. H.

occurred. The different rates at which thepreviously accumulated lead was eliminat-ed are illustrated most strikingly by theprolonged observations on subjects M.R.and E.B., and the difference between thesetwo subjects was especially pronounced,despite the (act that the totul quantitieso( load which they had retained (the onein four years, and' the other in two) werevery nearly identical If it be assumedthat the metabolic reactions of the twosubjects were much the same, theconclusion is almost inescapable that therespective rates of elimination dependedupon Muno factor associated with thelength o( time required to accumulate uliiveu iju.miity o[ lead in the- two in->lanves. Siith'a factor may U' \iMiali/eJ,in contemplating the evidence- tliat thelarge proportion uf the retained lead hadgone into the ossetms tissues of the two.subjects, iii which, in the two periods ottime, disproportionate quantities of theretained k-ad had found their way iutn thumore sluggishly metabolizing regions oi th--rt-spective bony structures. It has beenohsvrved at necropsy, that when kad hashem itliMirncd rapidly, it is unevenly distri-buted i:i a bone, being found in icl.itivelyhigh citncentration in the mure vascularand mure rapidly metabolizing areas; butwhen lead is absorbed very slowly, or at uluw U-vil intermittently, or when a lungperind of time has elapsed since the occur-ri-uce uf abnormal absorption, the concen-tration of lead in all parts of the bone tendsto be more nearly uniform (11). It may bonoted, in this relationship, that undernormal conditions, lead is found in higherconcentrations in the relatively ava*culurkmtf bones of the skeleton than in the flat(Table 16, Lecture 1), whereas the oppositerelationship obtains in fatal cases ot lendpoisoning (Table 27, Lecture HI).

It is of interest to examine Figure 11further, from the aspect .of the absolutelength of time that may be required for theelimination of a given quantify of lend re-tained in the body during q period ofabnormal absorption. This obvioully isrelated directly to the foregoing discussionof the rates of elimination, but from thepractical viewpoint, it is Important to thinkin definite temporal terms. It may be

observed that subject M.R. i l iminatc .very little of liia retained lead duritr.the period of 10 months ('actually o';:\7 to 10 milligrams'. This \vas (U:-,in part to the unfortunate circumstancethat, with the termination o( tuperiod of ' experimental ingotum. t h i <subject altered his mode of living s'nnowhat, and, as is likely to happen at sm.litimes, the quantity of lo.id in l i i s ' c l i . . ;changed. In this instance it wa> incu-av 1appreciably for approximately two mon',!.-.Despite this experiineiit.il variable, l i - " ' •ever, it was eviduit that tut- diminatK.:, i,;the lead which ho ha.l rc-Uined dnviii-g '.'.. •experiment wtmld re'-iuire a l"ii'j; t i . nSubject E.IV. "H t!i-:- t i l i i c r I1aud. lu-j:^:.promptly to climiinti- t'.c Ic.ul whiclt*.. .-hud retained. uu-.l he ci)ntimtfd l-.i clu s<« .,'.a fairly s-teaiiv but paJiuli.' di:.iiiiislii:..!.i\ito, fur about GO m'iiith>. alter u:i it,r.i..!period ot about two months ni ii!ati\i. ' .rapid loss. Dufitrjj the total period 1lunar months. S:)fi days1 he climin.i1.. .approximately 7'J uf tue 110 t:iiiiijrra!i'.s i -.-had aecumnlaCi-d in his body in 2) huv.:inrniths (half of tl?" retained li-.ul h.i-J \»\- •tliminated in 23 lunar m o j i l l i - f 1 . Ni i t!n : 'the other Mibjvt ts w.'.s i..!!-.twnl 1 • ,eiiouvih (the imnottance of d'Mti;^ v v ..not evident at thv t ime, and it would 1 . .•been difficult to do So in cither C.LS-. '.pr()\'id(* results which can nuw \>. <.pared with tho'-u obtained in t!»v t.i^( :subject F..\\. There is good ro.iMin. Itthe trends of the other two turvis . .»• ,! :view of the comparability ot the < • ! ; • •aspects of their metabolic patterns, tn i i.that subject I.F. reduced his retained U..-1by half in something more or li-s< t: ./.eight months, while subject M.U. c«-nMhardly have reached a similar state ith.it ;half of his experimentally induced '!)••!>burden") in much less than five yo.i:-These are, of course, rough estimates, !>• tthey provide some support for a " rule ->fthumb," which in the case of subject F l>is based on reasonably firm ground. Ormav state such a rule in his ca.sc. and m.:vperhaps apply it, with some reservation, toother situations involvinu approximatelytwo years of abnormal absorption to theeffect that about twice the length of timewas required to eliminate the accumuUtfJ

US

I !' H j, „ .,1 ».l Ml. A II I

' .K. t. ..i:.iu ;;. \,1 lead d' lr i ; .»

.actual ly ov.lvi'liis V/.IS (i ;'(.

't liviti-.' sfi-i-.j. . . '•:,tppcn at S'ld,.id ih In's tlic't; \\a.i ii:trc.,std-!y two ii iui i ihs.v.. ruble. h'uv-

-,- c l imin.itin;, c,f;nc'tl dur i i tv ; the• a I t n i u t i i i i f .r hand. I*;,;..;;

vl whivh In.-tu (I i ;:•» ,.t

uan initial

- pcrhdhe elmiiMaU1;!

0 milligrams he>ily i;. 23 l-iu.ir

.1 It-ad h.ul been:l.s . Neither of

followed Km'.;i" doiiij; si* wa»;i jt wi ' i tkl ha', ceither case; \->

. i.u\v be c <':'.•. •: in the cas'- cf•xl reason, i r^ i i i.1 turves-, and in

ot the o therLit:£7ns. tn inf'-r

.is retained leadre or less Hum

r M.H. could. state ..tlvat of

induced " bo;!y:lu» five >ears..:> estimates, butv for A ". rule of• of subject E.B.:n cround. Oneis case, and may.e reservation, to• approximatelyWrption to the•? length of timethe accumulated

. i-: t'1-^ 'iivcK-cd in its nc-C'imuhtinn.oilier subjects fall on one side or the

other of this estimate, ;ts will also thoseindividuals whose abnormal absorption oflead has resulted in accumulation over«hort or bug periods of time.

Another incidental feature of Figure 11j5 concerned with the lack of any visibleeffects in association with the " induceddietary changes" (which have been ze-ferrecf tc- previously) in the case of subjectM.R-, and with, the- correspondingly nega-tive effect of the indicated attempt at

i:." *l'ir l^ter, introducect intoexperiment only uf ter an inten'al of

tinu- Mili icient to pennit the normal clim-tuative pi'utesscs lu <lemonstrate theiropi-ratioii, Imt luf '>re there had been anyconsiderable diminution in the body bur-den ot lend, cnnsistfd in providnc! subjectM.fl. with a diet vt-iy lo\v in calcium; andin the administration uf ammoniumchloride in iuereasiny; dosage up to thepoint t.f tolerance. u \ e r a pcrind of sixweeks. The eflect, in terms of the elimina-tion of lead during this period, was clearlynegligible. It ha> been an accepted factfor some time that this type of cliininativerririmen is incflectu.tl, and mention isin.uh* t.f it Iieiv only for the sake of a fullrcpresvntatK'ti of the details of this experi-ment. This experimental procedure wasnot without point at the time it was under-take 11.

In the cn-iclitt oF the jrru ' ip of cxncri-meuts concerned with the infte.NtKiu ot Ic.ic:,opportunities presented themselves forseeking answers tu a nuinher of questionsthat are of interest to physiologist* and alsoto clinicians. Only a few of such questionswere pursued in a manner that required adeparture- from a simple and urduiAiyroutine of performance on the part of thesubjects. The data, on the other hand,have been ex.tmim-d by various means a:idin various relationships in search of signifi-cant items of evidence. They will be re-turned to again and again, no doubt, asfurther questions arise. One such proced-ure was that of examining thu dawobtained during the period following thetermination of the experimental ingc>M'.>ufit It-ad. "I his period, when lead was bci:!c;excreted in greater quantities than tl.oscbeing absorbed, was especially favourablefor flic determination of the relationshipbetween the urinary and the true alimen-tary excretion.

tables 21 and 22 disnlav the observedfacts, as well as the calculations and theassumptions, ou which arc based theestimation of ' the urinary and the alimen-tary excretion of lead by subjects M.Ii. andE.B. respectively, during the termi:u:lperiods of these two experiments. Thesteps in the calculations were those of vlsumming up the excess of the output "tlead of each subject over the intake, follow-

Table 21Lead Intake and Output of Normal Subject (M.R.l during the Period of 2SO

Days after the Termination of the Oral Administration of LeadIngested lead:

lu food and beveragesEliminated lead :

In urineIn feccs

15-»9 mgs.S3-43mgi.

TOTAL ...Excejj of Elimination

Excess excreted in urine ... ... 10-Umgs."Excess excreted by alimentary tract —2-8T mgi.

92- lSmys.

99-42 mgi.7 • 21 mgs.

TOTAL ... ... ... ... 7-24 mgs.' Arrived At by calculating what would hnve been th« normal urinary output for thi*

period, by multiplying the total volume of the urine during thi* period by ttw mean normalconcentration of lead In the urine of thil subjrct. and subtracting this product from tht totalamount of lead eliminated in the urine during this period.

119

'. *'**' • V^*?^^l^^v--

ing Ihc tr.TmmaUrm of the period of abnor-mal absorption, f < » i :i period ot time s^il i i-cicnt, presumably, tu i-anccl out the errorsof sampling of the food and feccs; (2) ofcalculating what would have been thenormal output of lead in the urine duringthis period, and subtracting this amountfrom the actual output during the period(the normal output was taken to be theproduct of the total volume of the urmoin litres, during this period, multiplied bythe mean normal concentration of lead inthe urine of the. subject as originallydetermined, expressed in the properdecimal of a milligram per litre); and (3) ofsubtracting the v.iluo in (2;, which willrepresent the excess of lead excreted in theurine, from the total excess, and regardingthi* difference us the excess of lead actuallyexcreted vi.i the alimentary tract. Thismethod is i.ot strictly precise, but it is cor-rect in principle, and can be expected toyield results that err only slightly, and arecertainly of the correct order of magnitude.According to Table 21, suhjecT M.R., ex-crettd a quantity of lead in his urine ofthe order of 7 to 10 mir. (dependent uponwhich value is accepted.' in excess of thatwhich was taken into bis bodv and

VL COM>IVIOV«

m ;jiiaible. in view of tlv.; r\ idmce lo \\] •-.!•.UU'i-.iion v.as called pievi/.usly, c.v.t air.'nii.il subject muy eliminate ii!::);o>:t-mately G mg. of lead (8 mg per yean duri;-.^such a period as this. The clcvathu t>'f(he output and the concentration <<f leadin the urine after the termination of tlu-•abnormal alisorption provides adeq'-iatee\icU-!ice, howe\-cr, of the excretion ol pre-viously absorbed lead in the urine. Thef j u a u t i t y of lead so excreted in excess nfthat normally excreted, is more nearly cor-rect, in all probability, than is the quanti tyindicated by the gross difference betweenintake and output, for th.e reason th.-.t,under the conditions nf these expermu-uti,errurs in the sampling of thft ur ine art U - j jnut r . r r iKts a!id smaller th.ui those a>^uci it-:cl\\itli tlie d'iplicatio;i of t l ic £i»o;.l c o t i M i m t i ld.u'ly. \Vc may reasonably take it. f roi i itliesv observations, tlicrel'jre, tliat .s.;ti>!'a.;-Inry evidence' has been iifiordt-d in Table-21 of tin.- excretion of the excess of Ic.idvia the urine, but that it has yielded m>\al id evidence that any of the n. taii ;-?illead was excreted by subject M.H. vi;: ti.valimentary tract.

Tin* evidence in Table 22 is 'diiieicnt.Subject E.B., when considered hi the s.t:;;.

Table 22Lead Intake and Output of Normal Subject ,E.B.) during the Period of

443 Days after the Termination of the Oral Administration of LeadIngested lead:

In food und beveragesEliminated lead :

In urineIn fecfts

143-20 nigs.

35-61 mgs.103-01

TOTAL ...Excels of Elimination

Excess excreted in urineExcess excreted by alimentary tract

TOTAL ...

19-13mgs.*2l'-32mgs.

40-45 mgi.

40*43 mgs.* Arrived at in die wnw manner at the corrrtponding value in Table 21.

absorbed during the period-of 250 dayswith which we are concerned in thisrelationship; during this same period he didnot excrete any of the retained lead byway of the alimentary tract. The actualexcess of the gross output of lead over thegross intake during this period was almost

manner as subject M.R. eliminated approxi-mately 40 milligrams of lead more than hetook in during the period of 44S days ofthese observations. The same methods ofcalculation indicate that approximatelyequal amounts of the retained lead wereexcreted in the urine and feces.

120

r flsw, v AvV *£'*•$ --i* v^ -'V.$*!:« -&V-i««A^&V. &-^r^v-.>^:^^-^.

HOnr.RT A KfMQC K I T It AM

iiv.ti.iii of

v.rt*i:>;j ot pie-he- unr.s. The•:d i:. tAccs? ofic re ::: rly cor*is the iiiuntity

rrev.ce I'ocwcen,e re.!?-::-, that.»* experiments,.' urin* arc- less

jod consumedtake ir. troni

.-, that J.Uisfac-••rded i:i Table

xce» of lead;:.is \-irldid nof tli* rttaiacd.t M.R. via the

22 is dirrerent.cd ::'. the same

doread

ir.:-r* tnon hef 445 di>f of\t mfthvdj ofapproximatelyA lead were

The meaning of these somewhat dispar-ate remits in the tv.-o iiistuncx.s i-1- notentirely certain. It st-ems improbable thatthere was any great difference in the opera-tion of the basic metabolic mechanisms ofthese two subjects. Rather, it is probablethat the principal difference in their excre-tory behaviour during these correspondingexperimental periods lay in the differencein the quantities of lead in active transit inthe two instances. \Ve have observed that,when the quantities of lead being excretedby certain patients wore quite largo, inthe absence of continuing respiratoryexposure to partfculatc lead compounds,the alimentary lead appeared to be appre-ciably trreatcr th.ui that which could beaccoiinlet! for by the lead ingested in food

and lu'veni^Vs. It set-ins likely therefore,that tin.: uiiiiii-iitary excretion or lead beginsto contribute to the total excretory process,when the lead in transit reaches a suitablethreshold, and that it contributes propor-tionally more, .is the quantity of leaa intransit increases. \\Y have observed per-sons whose true alimentary excretion oflead appeared to be three or four times thatin the urint* ^in the absence of renal impair-ment), and we have also seen others, as inthe case of subject M.R., whose alimentaryexcretion of lead appeared to be negligible.There is no doubt, of course, that lead isexcreted in the bile, but at its point of dis-charge into the alimentary tract it has alung way to 1:0 and a long time in which tobe absorbed before beiiu: evacuated.

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