LEAD POISONING

REVIEW

ARTICLE

LEAD

POISONING

Review

of

the

Literature

and

Report

on

45

Cases

By R. K. Byers, M.D.

Neurologi(al Dwi.sion, Children’s Hospital, Boston, (111(1 D(’parttlmcnt of Pediatrics,

llarcard ?IIC(liCal School

Floiiie visits and sonic of the chieniical analyses in

the Lead Imidustries Association.

ADDRESS: 300 Longwoocl Avenue, Boston 15, Massachusetts.

EAD POISONING continues to be an

impor-taut ciisease of childhood and, umnless

properly diiaglio)sedl amid treated, is capable

of producing dieathi or mental cnipplimig in

its victims. Because o)f this a review of the

recent literatumre on the subject imi relation

to occimrrence, eti( )logic factors, treatment

and prognosis, as vell as a report of our

exI)enieliCe with leadi poisoning seems

worthwhile.

REVIEW OF THE LITERATURE

The occurremice of lead poisoning appears

to be parallel to the interest iii and

pumblic-ity about the dlisease. In certain cities such

as Baltimore, where imiterest in the diisease

has lomig l)een fostered by the Board of

Health under Dr. Hummitington Williams,

many cases have been reported yearly. Imi

other cities, few or no cases have been

re-portedl imi the past, I)imt with awakenedi

in-terest substantial nunihers have been found.

Mellins and Jenkinsm reported 21 cases

di-agnoseci ill 1 year in a Chicago hospital

after the first case had beemi dielineatedi for

the staff by the Umiitedi States Public Health

Service; mio cases had been diagnosed

pre-vio)uslv for mamiy years. \uIcLaumghhin2

po)imitedl o)tmt that the nummber of cases

dli-agnosed and reported to the Board of

Health imi New York City hadi steadiily risen

from 1 in 1950 to 80 in 1954 consequent

upon publicity and the institution of

chem-ical determination of lead in blood and

urine by the Public Health Laboratory.

Awakening of medical interest in the

prob-1cm has l)een followed by simiiilar results

in other umnl)an areas.

Greenberg and Jacobziner,I workimig in

the New York City Department of Health,

point O)ut that pica miiay be umseci as a pul)hic

health case-finding method. They ask

par-ents about the occurremice of pic:t in babies

and small children umncler their care. Blood

samples for analysis as to lead comitent are

obtained from all infants exhibiting the

symptom, and if the level of lead imi the

blood reaches or exceeds 0.006 mg/100 ml

the children are referred for fimnther study

to their family physician or hospital with

the suspicion of lead poisonimig. Of 194

childiren exliibitimig pica, 14 prvecl to have

leadi poisomiimig and an additional 10

proh)-ably hiadi lead posonimig. No dieaths

curred.

There is fl() dlOubt that this is a valuable

contribution to the diagnosis andi care of

leadi po)iso)ning. However, it is important to

remember that pica is often denied by

par-ents of children whose intestinal tract

con-tains radio-opaque chips, andi that lead

poisoning has been reported to occur in tile

presence of levels of lead in the blood

lower than those cited, though the evidence

in this regard is not conclusive.

Etiologic Factors

By far the commonest source of lead

poisoning in children is leadl-containing

paint. Lead pigments4 (chrome-green,

chrome-yellow and white lead) have

be-come increasingly expensive since aboumt the

this paper were miiade possible through a grant from

time of World War I, and their use has

been gradumally restricted on this account,

but in the past century and an early part of

this century they were used extensively in

the United States on both interior trim and

on outside walls. These original coats have

often been buried under repainting, and if

chemical identification is to be made now,

paint samples must be obtained by scraping

to the underlying wood. Approximate

quantitative analysis for lead can be carried

out in virtually any chemical laboratory by

standard methods.

Even though in good condition, the

offending paint may be chewed by toddlers

off window sills, trim or furniture repainted

at home with lead-containing paint. Flaking

paint or crumbling painted plaster presents

a much greater hazard; Chisolm and

Harni-son5 have shown that the mean stool

co)n-tent of lead per 24 hours in a group of

children to whom such chips were available

was 44 mg, a figure many times in excess

of that usually regarded as dangerous in

industry. Exposures of such intensity

doubt-less are an important factor in the relative

frequency of lead encephalopathy in

chil-dren as compared to adults.

They also observed many secondary cases

O)f lead poisoning in families where several

children were expO)Sed to flaked paint, and

noted that the mouthing of such material

was an almost universal habit of young

children, not depending on pica, or aberrant

emiiotional o)r intellectual factors.

Emotional factors tending to pica for

paint, or other substances as well, are

dis-cussed in relation to lead poisoning by

Mehlins and Jenkins1 and by Millican et al.

Both sets o)f authors stress in the causation

of pica the importance of a disturbed

mother-child relationship in which the

mother, probably because of her own

imma-tunity, attempts to substitute continuming oral

satisfaction for more mature interpersonal

relations with the child. The usual pattern

of early infantile oral satisfaction tends,

according to) the first group of authors, to

became converted to the more aggressive

form of biting under such circumstances;

5 of 21 patients they studied hadi bitten

their mothers as well as chewing paint.

Socioeconomic deprivation is also reported

as umsual in both groumps.

An o)umtbreak of lead po)isoning clime to the

burning of discarded wooden

storage-battery boxes in the Scottish village of

Rotheram is described by Travers et al.

Six cases of lead poisoning, all in children,

with two dleathis, occurred. In two cases

severe jaundice accompanied the

intoxica-tion, though its genesis was not clearly

as-certained. The authors believed that all of

the affected children were poisoned by

play-ing in the contaminated ashes, rather than

by sublimation of the lead, becaumse older

members of the households escaped.

Valua-ble analysis of cadavers for lead are

pre-sented. In this co)untny similar exposures to

lead, though previously reported, have

be-come rare since storage-battery boxes are

now umsually plastic.

Biehusen and Pulaski call attention

again to the po)ssibility of lead poisoning

re-suiting from the retention of leaden objects

in the stomach where they can be acted

upon by the gastric juice. In thieir case,

symptoms and signs of poisoning began

aboumt the thirty-eighth day after a solder

medallion had been swallowed and retained

in the stomach and at the time of surgical

removal on the 59th day were quite severe.

The authors nO)te that this may be a risk

in the usual policy o)f watchfiml waiting in

cases of ingested foreign body, and they

make a plea for the complete identification

of sumch bodies. Other umnusumal sources of

lead are numeroums andi usually found only

after careful study of the home.

Lead poisoning has long been known to

be

commoner in summer thami winter. In

part, this is no doubt a reflection of the

greater chance of exposure to lead paint on

the part of children playing outdoors, as

compared to indoors. In addition, Rapoport

and Rubin” show that rats may be more

easily po)isoned by lead in their diet if

ex-pO)sedi to sunlight than if kept rndioors, and

suggest that just as vitamin D increases

REVIEW ARTICLE 587

it may increase the absorption of lead.

Dc Mellotm’ demonstrates an increased

excre-tion of co)prOpOrphynin in rabbits previously

poisoned by intraperitoneal lead and

sub-sequently exposed to ultraviolet light, and

suggests that such exposure either activates

the toxic action of lead on tissue metabolism

or causes an increased mobiliztion o)f

pre-formed porphyrins.

Physiology

The absorptiomi, dlistnibutio)n and storage

of lead have heen well descniheci by Aub

et al.11 and by Kehoe et al.12

Newly-absorbedi leadl is first dlistnibumted as lead

ciiphosphate to the soft tissumes, especially

l)rain, lungs, liver, spleen and marrow; from

these it is transferred to the bone where it

is stored as the virtually-insolumble lead

tn-phosphate. Without treatment the

comple-tiomi of the process may take several months

once the exposure to lead is interrupted.

Reversal of the process may take place in

the presence o)f acidosis and lead may be

redistributed to the soft tissumes.

Bessman and Layne’3 report that in

imn-treated lead poisoning the lead in the blood

is virtually all in the erythrocytes, and that

treatment with edathamil temporarily

re-verses the ratio between lead in

erythro-cytes and serum. Concentrations of lead in

blood are reported in health and disease

by Tanis’4 who points out that there is

con-siderable overlap o)f the values found in

no)rmal and poisoned children

(

0.03 to 0.06

mg/100 ml in normal children, and 0.04 to

0.11/100 ml in plumbism). Unfortunately,

this article gives none of the individimal case

histories; hence, it is not possible to judge

the basis for these statements.

Robinson et report on the levels of

lead in senumm, erythrocytes and whole

blood in a series of 103 infants and children

without a hiisto)ry c)f pica or lead poisoning.

Significant levels of lead are found in cord

blood, and in blood from babies under 6

miionths of age (range 0.005-0.031 mg/100

ml), while in older children levels between

0.003-0.054 mg/100 ml are recorded.

Chisolm and Harrison’ consider levels of

lead in the blood of 0.06 mg/100 ml as

probably abnormal and suggestive o)f lead

poisoning. In actual lead poisoning,

maxi-mumm levels well above those reported by

Tanis’4 are found.

Bradley et al.’7 report on values for lead

in the blood in 197 children with a positive

imninary test for coproporphyrin and 136

children in whom this test was negative.

They conclumde that a concentration of lead

of 0.05 mg/100 ml is the umpper limit of

nor-mal, because at this level the clinical

evi-dences of lead poisoning increase markedly.

Their data are not presented in sumfficient

detail to allow of careful appraisal, but

from the tables given it would appear that

some of the children with concemitrations of

lead in the blood below this level might

have lead poisoning. They point out that

several symptomless children with blood

concentration of lead above this level

simbse-qumently developed lead encephalopathy.

They note, as have others, that there is no)

one sign always present in lead poisoning,

and, in their summary, state that serious

lead intoxication can, in some

individ-uals, occimr at lower levels than 0.05 mgI

lOOmI.

Porphyrinunia in lead poiso)ning has been

recognized since the original report of de

Langen18 in 1948, and Maloof’9 imtihized its

occumrrence to detect unsuspected exposure

of industrial workers to lead, and indicated

a po)sitive correlation between

concentra-tion of lead in the blood and porphyrinumnia.

Chisolm and Harrison,2 using the amount

of lead excreted on the first day of

edathamil treatment as an index of lead

content in soft tissume, demonstrate a

posi-tive exponential relationship between this

value and the total daily output of

co)pro-porphyrin. They believe that urinary

coproporphynin excretion provides a

sensi-tive biochemical index of “metabolically

active” and presumably toxic lead in tissues.

Levels of coproporphynin output in normal

children are reported by these authors, by

Hsia and Page21 and by Rubin22 to fall

be-tween 0 and 75 g/24 hours for children

conoiitiomis other than lead poisoning can

elevate urinary copnoponphyrin oumtput.

The cumantity o)f lead involvedi in leadi

poisoning shoumlci probably be dlividledl for

purposes o)f discussion into that foummici in

the soft tissues amid thiat fotmnci in the

skele-tomi, because the former is believed to he

the actively toxic lead, while the latter is

tho)ught to) 1)e relatively inert unless

hiher-dtedl under metabolic stress. Aumb and

co-workersm m states that the skeletal analysis

of a 2-year-old dying of lead poisoning

con-tamed 1p)roximately 200 mg of lead.

Analysis of the tissume of two children clyimig

of actmte phtmmhisrn diumring the Rotherhani

oumtbreak allow Ofl to estimate the leadi

content of the soft tissues as in the

neigh-borhoodi of 15 trig. Chisolm and Harnison

made similar calculations from ciata of Aumb

et ailm aIldi Kehoe et (11.12 andi diata of their

own, amid arrived at an 1P1iroximation O)f 20

to 100 mug O)f leadi in the soft tissumes during

the acumte stage O)f leadi )oisOning and noted

that the removal of quantities of lead o)f this

order by edathamil is followed by shiarp

re-duction of the coproporphyninumria. The diata

of Aring and Trufant2 also) give valumes for

lead in this range.

Abnormalities of Porphyrin Metabolism in Lead Poisoning

While it is clear that the abnormalities of

porphyrin metabolism in lead poisoning are

far from umnderstoodi, two groups of

mecha-nisms, one responsible for the abnormal

cOncentratio)Ils of coproporphynin and

pro)toporphynin in erythrocytes, andi anothien

underlying urinary cOpro)porphyrrn, appear

to have been ehumciciateci. Watson2’ has

shown that coproporphynin concentration in

erythrocytes is closely allied to

hemato-poiesis and tends to he increased by the

same factors that cause reticulocytosis, and

that free protoporphynin in erythrocytes

seems to I)e increased by imifitmences (among

tliemn lead) tending to) interfere with the

biosynthesis of hieme from pro)toponphyrin.

In aciclitiomi they postulate some

interfer-ence by lead in the enzymatic cOnversio)n

of ervthrocyte coproporphyrin to

protopor-phynimi, thus accouhitilig for the great

in-crease imi 1)0th of these sul)stanCes in the

erythirocytes.

Eniksemi2 has shown 1)\’ imi-vitro eXI)eni

nients with immiiature ral)I)it erytliro)cytes

amid! cluck erythrocytes that the formation

of protoporphvnimi and hiemne by these cells

is intemferedi with by lead, and that of these

t\V() the ciisproportiomiately larger effect is

on hiemne fonniation.

Both \Vatson amid Eniksen believe that

lead miiumst in some way interfere with

porpiiynimi nietal)olism imi tissumes other than

blood to accoimmit for the quantity of

cOpnO1)0r1)hyrihi in the urine.

Aldrich et (ll. dlescrii)e the metabolic

i)rec1mrsrs o)f the porphvrimis amidi detail their

formation from succinic acid and glycine

suitably labeledi with C’’ and they suggest

that leadi may have irregimlar ciehiterioums

effects omi the l)iosymithiesis o)f even these

early steps in porphyrin formiiatiomi. They’

agree that the amTlOtmlit of urinary excretio)fl

of coproporphyrimi coumldi not be accounted

for by the difficulties I1 henie formation

alone amii Poimit out thiat excessive

copro-porphynimiumnia occurs in rheumatic fever,

pohomyehitis, iron-deficiency anemia,

alco-hoh ingestion and cirrhosis o)f the liver. In

these situatio)Iis the coproporphyrimi in the

urine is type III, the same as in lead

poison-ing. Pernicious aneniia and infectious

hepa-titis are accOmnl)anledi by type I

co)prOpOr-phynin in the urine. Thus many body tissues

other than those involvedi in hematopoiesis

cami, whemi diamliagedi, cause excessive

copro-por)hiyninunia.

Pharmacology of Edathamil

Ediathamil diisodhimm calcium as adapted

to the removal of heavy metals from the

body is reported upon by a number of

mdii-vicluals in the report of a conference heldi

at the Iass.ichusetts General Hospital.27

Rubin shows that the comiibination O)f lead

dhidi eclathamil cami he 1)ro)ken clown by the

bodly and that o)Iil\’ al)Out 70f O)f a dose

of eciathamil (iisodiiimfli leadi injected into) a

rabbit cami be recovered in the urine in 24

REVIEW ARTICLE 589

and eciathainil given 2 hours to 4 days

later, only about 40% of the lead can be

recovered in the excneta imi 24 clays, and

also if lead acetate alone is given only

aboimt 5% is excreted imi the same time.

Vir-tually all the leadi excreted is in the urine.

i’sIaisomi findis that calciumm disoclium

eda-thamil is poorly absorbedi from the

gastro-intestimial tract, hut that the lead chielate is

rapidly absorbed.

Foreman amid Tnumjillo,2s using C14_lahelledi

eciathamil, show that this substance rapidly

diiffuses into all the body tissues except the

cerebrospinal fluid and erythnocytes.

Toxic daniage to the kidney tumhules by

edathamil is reportedi by Foreman et al.2

in experiniental animals. Large doses for a

short time, on smaller closes given

continu-oimslv over a lomiger peniodl prociumce

hy-dropic changes in the tthI)ular cells, which

these experimemiters report as reversible.

Dudley et a!. :c report fatal tubumlar ciamage

in two I)1tient5 treated with several times

the necornmemiciedi dose of edlathamil

tetra-sodium for 1)eniodls of 9 anci 12 clays,

re-spectively, for the relief O)f hypercalcemia

secondlary to skeletal carcinomatosis.

Chis-olIn andi Hannisomi” use dioses of eclathamil

of 75 mrig/kg/24 hotmrs, given either

intra-muscimlarly as 20% solution with procaine

0.5%, or imitravenoumsly; andi continued 5 to

7 days. In one of their patients, who was

oliguric throughout the hospital course and

died on the fourth clay of treatment, lesions

similar to) those dlescnibedi by Dudiley

et a!. so were found. The authors believe that

oligumria caumsed unexpectedly high

concen-trations of edathamil to accumulate in the

blood with the produmction of tumbulan

dam-age. They advise caution in the use of the

drug when urine output falls below 200 to

300 mI/day. In the same paper Chisolm

and Harrison paint out the prompt

diisap-1)earalice of lead from the stO)o)l5 of children

when they are irevemitedl from eating lead

ahidi are treated with edlathamil

intramumscu-larly or intravenously.

Kneller et (11.71 report on the treatmemit of

a 20-month-old infant suffering from lead

poisoning with edathamil 0.5 gin in 100 ml

of no)nmnal sahimie sohumtiomi by siml)cumtamieous

clysis three times a day. During treatment

the chiildl cievelopeci pallor, chattering of the

teeth, lethargy andi ataxia. Dumring the

epi-sodle calcium iii the serum was foummici to he

16 mg/100 lTd. The symptoms suml)sidledi 011

the withdrawal of edathiamnil and use of

glum-cose solution to Pnmte ditmresis, and a diay

on two later thie serumm calcitmm was 11 mgI

100 ml. During treatment the bloodl level

O)f lead dlecreasedl from abnormal to normal

over a 3-clay period, hut with the cessation

of treatment increased again to abnormal

levels. The variations in senumm calcium

re-main umnexplaineci, and the symptoms do

not 1pI)ear to) ie clearly related! to the

calcium level.

Diagnosis of Lead Poisoning

The climiical criteria for the dliagnosms of

lead! poisoning have not chiangedi over the

years, bumt so mamiy erroneous diagnoses are

encoumnterecl in hospital recordis that it is

impo)rtant to) emphasize that no one sign

of lead! poisoning is pathognomomiic-that

all can be simulated I)y other diseases and

conciitions, and that in \vell-establishedl lead

poisoning any O)f them can be absent more

Or less temporarily.

Of greatest importance remains the

chemical identification of a source of lead!;

flaking laint vithi as little as 2 on 3% lead

or painted! surfaces containing 10% lead, if

chewed, are certainly hazarcioums and

ac-count for well over 90% of childhood!

plumbism.

Next ill importance is proof of

ahsorp-tion of lead! as shown by repeated

dc-termination of lead! in time blood on umninary

excretion estimations. Values of 0.06 mgI

100 ml or over for lead in blood are

gen-erally considered! pathological. Sawyer et

32 and Schmitt et (ll.3: have shown that

a single determination of lead in blood in

normal indiivid!uals may be temporarily

above levels generally regarded as to)xic

from vaniouis causes. Urinary excretion of

lead in amounts oven 80 g/24 hours was

showmi by Byers et al.” to occur only in lead!

defec-590

tive renal function may resumlt in a normal

level

of excretion. Urinary concentration of

lead, because of the markedly variable

24-houmr urinary volume of children is an

imnrehiable index. Extreme precautions to)

prevent co)ntammnatmon of the urine with

lead are required to get a representative

analysis, and collections virtually requmire

hiospitahzation.

From the point of view of the clinician, a

high level of suspicion is important in

arriv-ing at the diagnosis. Pica for paint is often

unobserved or denied by the parents bimt is

objectively identifiable by the finding of

radio-opaque material in the gut. Vomiting,

constipation and pallor are the usumal early

symptoms. Encephalopathy with

irnita-bility, coma, convulsions and the usual

evi-dence O)f increased intracranial pressure

may develop very rapidly on may impend

for weeks, as may peripheral neuritis.

Laboratory evidences are: 1) microcytic

anemia with stippling; 2) roentgenologic

evidence of radio-opaque material in the

gut and of condensation of the lines of

provisional calcification of the long bones, in

infants, toddlers and young children; 3)

dis-turbances of porphyrin metabolism, most

easily identified by the qualitative test for

umninary coproporphynin, bumt also

demonstra-ble as increased free protoporphynin in

erythrocytes (Watson et al.5) and

qumanti-tatively as an increase in the 24-hour

ex-cretion of coproporphynin above 250 .g/

24 houmrs (Chisolm and Harrison1) where

the required laboratory methods are

availa-bhe; 4) glycosumria with a normal blood

sugar, and amino-acidunia (both signs of

renal tubular damage6); tnd 5) elevation of

the total protein and occasionally of the cell

count and pressure of the cerebrospinal

fluid.

In the presence of

chemically-demonstra-ble exposure tO) lead, the presence of

symp-toms or signs from two) of the above

catalogued groups is sufficient evidence to

establish poisoning. Without chemical proof

of exposure, symptoms or signs from three of

the organ groumps above usimally establish

the diagnosis reliably (Byers and Maloof7).

Further chagnostic subdivision is sumggested!

by Chiisolm and Harrison1 in five categories

varying in severity: 1) normal exposed;

2) asymptomatic, increased lead exposure

(

in this group abnormal levels for lead in

blood are found and occasionally

copro-porphiynin excretion in the urine is

in-creased); 3) lead intoxication without

encephalopathy (cenebrospinal fluid

nor-mal); 4) lead encephalopathy, mild

(cere-brospinal fluid abnormal); and 5) lead

encephalopathy, severe (in which

convul-sions and coma are prominent features).

Chisolm et have called attention to

a combination of rachitic changes in

rO)entgenograms of the long bones,

amino-aciduiria, andi glycosuria, suggestive of the

de Toni-Fanconi syndrome and probably

related to disturbance of enzymes in the

renal tubules by lead.

Although the diagnosis of lead! poisoning

can undoubtedly be made on clinical

grounds alone, the implications of

after-care are sufficiently troublesome socially

(and in some states legally) that chemical

proof of the intoxication is always

desina-ble, and should be sought on rather slender

indications such as a history of pica.

Treatment

All authors agree that edathamil given

intravenously or intramuscularly in doses

of 75 mg/kg/day, produces amelioration of

the symptoms and signs of lead poisoning

beginning 36 to 72 hours after the

institu-tion of treatment, and that the daily

excre-tio)n of lead in the urine is increased up to

40-fold by its use.

Bessman et discuss time theoretic

basis for the use of edathamil, and note the

relatively prompt improvement in the

symp-tomiis of lead intoxication consequment on its

use. They calculate that 1.8 mg o)f lead are

excreted for each 500 mg of edlathamil

calcium disodium given. They note no

toxicity when the drug is given

intraven-ously in 0.5 gm doses every 8 hours to

chiildren in coumrses of 3-clays d!imration, and

repeated if required after a 3-day free

591

was given to one patient by Byers and

Maloof’T because of persistent neuro)logic

symptoms. Chisolmn and Harrisontm6 use

5-to 7-day courses originally, and! a second

or third course after an interval of 10 to

14 days: if the blood lead rises above 0.1

mg/iOO ml, if the 24-houmr urinary

excre-tio)n of coproporphynin exceeds 250 .g/24

hours, or if neuirologic symptoms persist.

They note that, during subsequment acute

infection, urinary output of cOpro)porphynin

increases sharply although levels of blood

lead do not, and agree with Byers and

Maloof7 that treatment again with

eda-thamil under such conditions may be

advisable.

Chisolm and Harrison’ compare their 36

cases treated with edathamil with 33 cases

treated with dimercaprol (BAL) in

previ-ous years, andl show that in the latter

re-covery from the acute phases of lead

poison-ing is as ra1)id as in the former, but that a

fan larger proportion of the cases treated

with BAL show severe central nervous

system sequelae, i.e., 12 out of 33 as

com-pared to 4 out of 36 for edathamil. The

cases treated with BAL were perhaps not

as well protected from re-exposumne to lead

after treatment as the cases treated with

edathamil. They emphasize the need of

pro-tecting the children from re-exposure to

lead by adequately dc-leading the home

premises or by removal of the child to new

surroundings or a foster home.

Although oral use of edathamil was

men-tioned by Sidbury et al.4 in their original

cc)mmunication, a systematic attempt at oral

use is reported by Bradley amid Powell,’

who state that, while umrinary excretion of

lead is increased three- to ten-fold with

oral administration, it is so mumch less

effi-cient than intravenous or intramuscular as

to make its use in acumte cases unwarranted.

Renal Complication

The possibility that plumbism in

child-hood may produce a type of nephrosclerosis

resulting in death in middle-adult life is

raised in a series of articles by

Hender-son4245 from Australia. In tropical

Queens-REVIEW ARTICLE

Byers and Maloof7 use the drug in doses

of 65 mg/kg/day intravenoimsly (1 gm/iS

kg/day), given in two equal doses

approxi-mately 12 hours apart in 100 to 200 ml of 5%

dextrose in water. They note the increase in

lead excretio)n, rapid decline in

copropor-phynimiumnia, and imi four cases retumrii to)

nor-mal o)f elevated total protein in

cerebro-spinal fluid over periods of 3 to 9 days.

They also note a return of

coproporphyr-inumnia a clay or two after cessation of

treat-ment, even though the patient remained in

the hospital protected from exposure to

lead, and! attribute this to mobilization of

skeletal sto)res of lead and its transfer to

soft tissume.

Melhins and! Jenkinsm report on tile

treat-ment of lead poisoning with edathamil in

21 children, with five deaths. At follow-up,

6 to 8 mo)nths later, one child was

psycho-logically normal, the remainder showed

emotional, intellectual or social impairment,

with visulomo)tor impairment common in

those with mental ages over 19 months.

Though language was flument in many,

con-ceptual expression was frequently impaired.

It is not clear how well these children were

protected from lead after returning home

from the hospital.

Chisolm and Harrison16 report on a series

of 36 children with lead encephalopathy, of

whom 22 had mild disease and 14, severe;

among the latter, 5 deaths occurred or an

over-all death rate of approximately 14%.

They thought that, while edathamil may

have improved the lot of the survivors,

it did! not decrease the death rate. They

report lead excretio)n to be as good when

edathamil is given intramuscumlarly in 20%

solution with 0.5% procaine as when it is

given imitravenously. Among the 26

sumrviv-ors followed for 2 years or more and

adequmately protected from lead, 18 are

regarded as normal, 4 as mildly impaired

intellectually, and 4 as gro)ssly damaged.

The number of courses of treatment

ad-vised varies. With the shorter 3-day courses,

a second 3-day course (after a rest period

of 3 or 4 days) usually produces a large

592

land, imithe period from about 1870 umitil it

‘as forhiciclemi l)y law in the 1920’s, houses

were 1)limltedi with white lead 1)aimit,

I)e-cause this reflected as much sum and heat

as 1)OsSible, and because umndier the

conch-tions of tropical sun sumch paimit had the

best wearing qualities. Under the inflimence

of the sumi, the paint (linseed! oil and! vliite

lead) gradually P\’ciered! off, and childiren

playimig o)n the verandlas of such houses

were constantly exposed to this source of

leach as it dusted c)ff omi their clothes llidl

hands. Nyc4 reportedi o)n this imi the 1920’s

and many clinically diagnosec! cases were

reported, a few with chemical

comifirma-tiomi. Hendlerson has made a follow-up stuc!y

of 401 such children diagnosed between

1915 and 1935. Of these, 165 were known to

have c!iec!, and! chronic nephnitis or vascular

diisease was given as the cause of dleathi imi

the

mec!ical death certificates of 108 of

them. Of 187 alive and located, 17 have

hypertension and! albuminuiria and 3

hyper-tension alone; 49 individluals coumldi not be

traced. The 108 remial-vascumlar deaths

oc-cumrredi 6 to 34 years after the d!iagnoses of

plumbism were established. These deaths

are far in excess of the expected! rate from

these causes in the given ages in Aimstrahia.

Henderson’s second contribution is a

stumciy of chronic nephnitis in Qumeensland!,

and! a great excess of deaths in youmng

mdi-vic!umals who were probably exposed! to a

nephirotoxic sumbstance between 1879 and

1920 is shown. An analysis of the lead

con-tent o)f the hones of individluals d!ying of

chronic nephiritis in Queensland is given in

his third paper. The mean lead content of

the bones of such individluals is more than

twice as high as that in a control groump, and

in many of these expostmre to white lead in

childihood! was acknowledgec! by history.

The clinical signs of this type of

nephro-sclerosis are reported by Henderson to be a

tendency to fixation of specific gravity in

the umnine, mild albumminunia and later

hyper-tension with remial failure as an acute

termi-nal episode. A study of the kidney

pa-thology by Henderson is in progress.

Though reported in other coumntnies

(Oh-yen,47 Legge amid Goacihy”) observers in

the United! States do not report such

fimici-ings. Possibl’ chiffenemices iii degree amid

length of CX1)OSUF milay cumitnibumte to the

apparent c!iffenence ill outcomiie, and

I)O)ssi-bly the greater number exposed to) risk in

Aumstrahia in the past has given greater

op-portumnity for the identification of the

nephrotoxic symicirome. As po)intedi out h)y

Henderson,4’ American industrial

hygien-ists have tend!edl to deny the existemice of

chronic nephiritis chime to leach, l)ult this may

well he becaimse of effective control

meas-ures introc!umcecl before amiyone became

in-terested in the renal comisequmences o)f

1huimbism. At any rate a long-term

follow-imp stumdiy of this aspect of the problem seems

clearly ind!icated.

Summary of Literature

A review of some of the recent literature

on lead poisoning in childhood confirms the

impression that lead! pOiso)nilig will be

chiag-nosed only when a high degree of suspicion

as to its presence exists. The etiologic

factors includ!e: 1) the availability of leac!;

2) the developmental level of the affected

children; 3) the iersomial relationships

be-tween the I)aremits and childi; amid 4) social

and financial clepnivatiomi. Factors affecting

absorption, distribution amid! storage of lead

have been long understood; it appears that

disturbances O)f porphyrin metabolism are

importantly related td) the portion of lead

retained in the soft tissue andl are probab1y

to)xicologically important. Quantitative data

sumggest that the total lead! in the body may

be in the neighhorhoodi of several hundred!

milligrams, and that leach in soft tissues, the

remo)val of which is probably imngent, may

range betweemi 15 amid 100 mg.

Ed!athamil is a sumccessfiml chelating agent

for removing lead from the soft tissumes and!

allowing its excretiomi via the umrimie. It is,

however, cal)able of releasing lead to soft

tissumes vhien given to) exl)erimnental animals

as the leadi chelate. Intravenous or

intra-muscular edathiamil is niore effective than

oral edathamil in the acute stage; whether

treat-REVIEW ARTICLE 593

45

ment to) rid the hodhy of its skeletal stores

more quickly is discussed! later. If the drumg

is used! in too) large or too persistent dosage,

it may endanger the kidney tubules.

Hyper-calcemia is recorded in one case treated

with appropriate d!oses of the dnumg.

Diagnostic criteria have been so)mewhat

5O)hidhfied by several observers but it is clear

that no omie diagnostic tool is ad!equmate.

Treatment of acuite cases with

intrave-110)1.15 or imitramnumscuilar ec!athiamil has

result-Cd! ifl rapid resolution of the symptoms and

signs of lead poisoning after a latent period!

of 1 or 2 days, diulring which supportive

treatmnemit with or withoumt cranial

d!eccm-pression may l)e vital. The d!eath rate is

no)t appreciably altered! by ec!atliamil

therapy, but effective neumrologic recovery is

prl)al)ly more common.

In ad!ditiomi to the neurologic sequelae the

possibility o)f late nephirosclerotic dl image,

‘ears after lead poisoning, has beemi raised!

imi Australia where exposure was probably

relatively co)mistamit and prolonged.

REPORT OF AUTHOR’S EXPERIENCE

Some of the problems posed by the

re-vie\T of tile literature have been stumdied by

design, and ome by accident, at the

Chil-dremis Hosptal imi Boston during thie period!

from September 1952, vhemi edathiamil first

became available to us throumgh the

kind-ness of the Riken Laboratories, to

Septem-her, 1955. Through the kindness of the

Lead Industries Association we hiave been

able to visit the homes of most of the

in-vohvedl children, obtain samiiples of paimit or

other soumrces of lead and advise on thie

steps necessary to) lirotect the childiremi from

lead! on their return home.

Patient Material

During this 3-year period, 65 cliagmioses of

lead poisomiing were recorded imi the files of the

Childlremi’s Hospital of Boston. Of these, 10

were defimiitelv disproved by home visits,

chemical analysis of umrimie and chimiical

examn-inatiomi. Iii 10 miiore cases the data accumulated

‘as insufficient for jumdgmemit and these are

cx-eluded from further discumssion here.

Imi the nemainimig 45 cases the diagnosis of

lead poisomiing depended on the chemical

idemi-tificatiomi of the source (39 cases), chemiiical

identificatiomi of lead imi amoumits of 80 ig or

more

u-i

a 24-hour unimie sample (:38 cases

in-eluding 3 of the 6 not proven as to source), a

comistellation O)f clinical svmpto)mns indicative of the disease iii all, amid miecropsy in 4

(imichmcl-imig 2 not previously identified chemica11). Omie

child was imicludecl whose history was of pica

f:r paint at a lange miummber of houses, whose

svmnptcms inclumdeci irritability amid vomitimig,

hemoglobimi of 9 gm’ 100 ml with stippled

ervthrocvtes, abmiormal coproporphvrins imi

umnine l)y qualitative test, amid roemitgemiogramns

of long bones co)mpatihle with lead poisoning.

Hen imrinany leadl output was iii the normal

range at the time of hospital admission, but

she had moved to a new neighborhood a few

weeks before. With edlatliamil treatmiient the

imnimianv leach output rtse to 1 ,700 p.g/24 hr amid the porph’rinuria cleared.

Observations

MENTAL STATUS BEFORE PLUMBISM:

The endowment of this groimp of children

prior to plumbisrn was estimated! by home

visits, psychologic interview and! medical

history at the time of admissiomi to the

hos-pital. Inquiry imicluciedi the history of

preg-nancy, dhehivery, neonatal status, motor

dc-velopment, adhaptive behavior and language

behavior. The clinical psychologic

esti-mate of the children is shown in Table I.

SEASONAL INCIDENCE: Seasonal incidence

in oumr cases (Fig. 1) corresponded with that

previo)usly described for the north

temper-ate zone; 36 of the cases occurred in the

6-month period!, May 1 to November 1, and!

12 cases during July. The annual occurrence

was 22, ii and 12 cases.

AGE: The ages of the affected children

‘FABLE I

ESTIMATE 01’ Psuom.ooie STATIS o PATIENTS Pitiomt

TO LEAI) I)msoN1N(; (( )BTAINEO BY IImSTOJIY)

Normal 39

Ientai1y inmj)aire(i

J FM A M J J A S 0 N 0

20

6

2

4

AGE (years)

Fic. 2. Distribution of cases by age. 2

l0

8

6

4

2

Fm. 1. I)istribution of cases by miionth of adniissiomi

to hospital.

(Fig. 2) varied from 5 months to 7 years,

with 30 chilc!ren falling in the range

be-tween 1 and 3 years. Two of the three 5- to

7-year-old children were clearly retarded

mentally pnio)r to poisoning, and pica was a

manifestation of their retardation. No

esti-mate of the pre-poisoning status of the

5-month-old infant was attempted, and

clearly estimates of the mentality of the

1-to 3-year-old group by historical analysis

are inc!ividuially open to doubt, but for the

group as a whole are believed fairly

repre-sentative.

SOURCE OF LEAD: The soumrce of lead in

36 instances was proven to be paint; in 12

instances this was interior paint, always in

rather antiquated housing as in one instance

twins were affected in a Victorian suburban

mansion; the remainder were in definitely

depressed slum areas. Outside paint, often

flaking from porch railings, doors or outside

walls, was the source in 22 cases. One pair

of brothers was poisoned by the ashes of

hummed paint falling into their play yard

when their home was being prepared for

repainting. Flaking, rubber-base, deck paint

used on ceilings was the source in two

in-stances.

An umiusual sotmrce of lead in omie child

appears to have h)eemi a font of molten

type-metal in her father’s printing shop, beside

which she slept for warmth during her first,

second and third winters. No amialyses of air in

the shop were made, but no other source of

lead could be foumid iii the child’s environment.

Her umnimiary output of lead on imitravenous

edathamil during her first day in the hospital

was 5,104 p.g/24 hours. Her two older brothers,

9 and 7 years of age, reared in the same

fashion shoveci imitellectual irregularities and

difficult’ in academic learmiing compatible with

old cerebral injumrv (possibly dime to lead

poisomi-ing) but mio clear evidemice of lead poisomiing

was found in them.

The 5-month-old infant was a breast-fed,

Chinese baby, brought to) the hospital imi deep

coma amid with very obligatory tonic

neck-reflexes ( Fig. 3). Her mother excreted 102 ug

of leach in omie 24-hour umnine sample and in

REVIEW ARTICLE

“S.

II

595

J

/

#{149}/

‘,.

1’!

I

I’

1’

A

FIG. :3. Tonic neck-reflexes in coniatose 5-miionth-old Chimiese infant with severe

lead encephalitis.

‘

:1

‘is

0.3 to 0.8 J.g/nil. Two samples of this womami’s

milk were chemiiicahly free of lead. As soon as

sti)p1edl cells were foumld imi the baby’s blood

smear, and a total proteimi of 440 mg/’lOO ml

‘vas reported in the cerebrospimial flumid,

treat-merit with intravemioums edatbamil was begumi.

Imi time first 4 days of treatment, this 18-lb baby

excreted 12.7 rng of lead in the urine. The

cerebrospimial fluid protein was normal omi the

fourteemith day of treatmemit, after a second

course of edathamil; and at 3)4 years of

age she is psychologically amid mieumrologically

imitact. No soumrce of the lead was ever foummid,

but there is a fair suispiciomi that the mother

had used ami oniemital bramid of dumstimig powder

which comitaimiech white leadl. A subsequent

pregmiamicy has resumlted in a miormal baby, and

the mother no lomiger excretes excessive

amoumnts of lead.

No soumrce o)f lead was found in another

chilc! who) died 6 houmrs after adimission, and!

in whom the diagnosis was confirmed at

necropsy. The father stated that the pipes

in the home were leac!en, I)ut the house

burned down the day after the patient was

admitted to the hopsital, so no chemical

studies could be made. The three other

members of the family shovech no evidence

of lead poisoning.

In seven other chilc!ren mio source of lead

was dhscoveredh, in one a home visit was

re-fused! anc! six homes were too chistant for

visiting.

EMOTIONAL FACTORS: No formal attempt

at emotional stuld!y of the parent-chiild

re-lationship was mad!e, but by anc! large the

children came from imndlerprivileged homes,

and deprivation socially, financially and

emotionally was obvious, save for two

well-to-do families, each with an affectech

pair of twins.

FAMILIAL OCCURRENCE: This series

con-tains three sets of twins, both affected by

lead poisoning, anch three additional

sib-ships with multiple cases involving three,

two and three children respectively, or arm

occurrence of seven proven secondary cases.

Thus family stumcly is eminently wo)rthwhile

in case finding.

ENCEPHALOPATHY, RE-EXPOSURE: It has

been shown repeatedly that the prognosis

for intellectual competence in lead

0 Supplied by Biker Laboratories, Imic. of acute emicephalopathiy anc! by re-exposure

to leadh after treatmiiemit.’ ‘ Sevemiteen of the

forty-five pttiemits in the present series had

acute encephalopathy as shown by exh

ibi-tiomi of tWO) of the following symptoms or

sigmis: a) various chegrees of cloudhing o)f

consciotmsness; I)) cOnvuilSiOlis; c) slowed

pulse or respiration; ci) cho)ked! optic chiscs;

e) elevated! 1)roteimi imi the cerebrospinal fluid.

After treatment bach beemi cO)mlil)leted, it

Proved imiipossihile to Protect 8 of the 45

children from further exposure to lead,

usum-ally becaumse they moved from apartmemit to

(11)(lrtmnent, o)r because the famriihies lived at

such a dlistance as to be beyond! control.

TREATMENT: Treatment, imi all bumt two or

three individhuals (to) be d!escnibed later), was

carriec! oumt by intravenous or intramumscular

misc of edathamil calcium dhisodiumm,#{176} 65

mg/kg/c!ay, dhividhed! imito) tvo closes. The

intravenous solution was given over a

pe-nod of 1 to) 2 hours in 100 ml of 5% dhextrose

in water; the intraniumscular medication was

givemi in 20% solutiomi in normal sahimie

solum-tiomi with 0.5w procaine. Three- to foumr-diay

courses of treatmiient were given, altennatimig

with 4-dlay rest 1)erio)d!s. All cases receivedh

at least two courses of therapy; 5 cases in

whiomii proteimi remnaimiech elevated! imi the

cerei)ro)spinal fluic! on in whom a strikingly

I)Ositive test for urinary coproporphynimi was

still evid!emit at the end! o)f the second course,

received a third! course. Seven children were

given a seconch hospitalization for treatment

when co)proporphynnhulria again became

in-temise as jumchgech by qumahitative tests at

van-oils I)enio)dhs of months after discharge.

Multiple examinations o)f total pnotemi in

the cerebrospinal fluid are recordied! in eight

patients. In o)mie, diaily o)bservatioli d!uring

the acimmmiistratmon of ec!athamil showed

36.5 mg/iOO ml on admission, 118 mg/iOO

ml after 24 hioumrs of treatment, 71 mg/iOO

ml 0)11 tIle SeCo)ndi day of treatment, and 41

mg/i00 ml 0)11 the third clay. This patient

bach rad!iO-o)ptqule material in lien gumt by

roentgenographiic examination oni

ad!mis-siomi, and tneatmemit was begun immediately

withoimt amly attemiipt to emiipty the

gastro-imitestimial tract. The fimidings suggest that

imitravemio)us treatniemi t vith ed!athanhil mnay

cause an increase imi ai)sorptiomi of leach

when soiiie is 1)resent imi the gut, its transfer

to vulnerable soft tissues, anch might play a

part in the latemit period betweemi the

begin-ning of treatment amich the improvement of

sYmptoms . Other explamiations are o)hvioums.

At any rate, we have not repeated! the

oh-servation bimt have attempted to evacuate

the I)o)Wel by eneniata amid mild! laxatives

prior to the use of ec!athiamil. This child

has c!one very well intellectumally since

clis-cli arge.

In five other chilc!nemi, cerebrospimial flumici

proteimis before treatment ramigec! between

135 and 73 mg/100 ml, and when observed

again after treatment, 5 or 6 clays later, the

levels were between 40 amid 7.5 mg/iOO ml.

In tWO) chilciremi, proteins were still elevated!

to 87 and 62 mg/iOO ml, respectively, on

the seventh and sixteenth clays of treatment.

No imitervening observatiomis were mache, and

no p.irticumlar expiamiation of the slowness of

resl)OliSe to treatmiient was evident. Both

were treated with thiinc! courses of

edlatha-mil. The first Fats beemi followed! regularly

for 33 years, amid diuning time initial 2 to 2%

years after leach oisomiiiig she showed

men-tal irregularities which diminished until 3%

years after treatment she appears to he

psy-chologically intact. The secomic! child, 6

nioiithis after treatment, was d!efiliitely

re-tanclecl as comparec! to) his unaffected twin,

but since that visit the famiiily has not been

heard! front and has moved from its origimial

address.

In t\V() instamices, cranial decompression

by remo)val of extensive portions of

tern-1)0r1 and! parietal bones was canned out by

neumrosumrgical cohleagumes, Drs. Ingrahiam

amid! Matson, because of evicience of critical

increased! imitracranial pressure. The hone

‘as maintained imi sterile frozen state and

replaced after the suibsic!ence of the

cere-bral swelling. Both patiemits sumrvived!, one

with slow but satisfactory recovery from

REVIEW ARTICLE 597

I)enllilmiemit gross mnemital claniage.

Oral use d)f eclathamiiil was explored froni

three 1)Oimits of view : first, as to its possible

efficacy imi amiielio)ratimig thw effect of lead!

po)iso)miimig after treatmnemit for the acute stage

was coiiipletecl; second!lV, aS ami alternative

method for the treatment of the acute

dis-ease; amic! thirdly, by comriparing the effect

of oral vensuis intravemious or imitramiiimscular

use of eclathamiiil o)mi )orj)hynimi metabol:sm

in the acumte stage.

Imi the first imistance, six children, vhiere

the I)O)SSiI)ihitv of re-imigesta)n of lead! after

completion of hospital treatment as outtlined!

above va clefimiitely excluded! by special

circumstamices, were given ec!athamil tablets

1))’ ITh)uthi in closes o)f 0.75 to 1.5 gm daily.

They were seen miiomithly, amic! freshly voided

umnimie saIill)les were qumalitatively examined

for coproporphyrimi by acidifying, extracting

vith an approximately edium.sl volume of

ether for % hour at room temperature and

examlimning the ether haven under a \Vooc!’s

tmltraviolet-rav lamnp for cherry red fltm

)res-cemice. Temi O)thier children, vhrn liddl been

similarly treatec! in the acute stage, were

followed vithoumt treatniemit O)thier than

re-moval of leach from thieir environment.

Figtmre 4 shiO)\Vs that cOpro)porphiyrmiuria

per-sisted! quite comparably imi the two groups,

i.e., from 4 to) 17 momiths imi the treated

group amid 3 to 15 mouths in the umitreateci

group. Oral ac!ministratiomi of eclathamnil is

thierefore mml)ortant to shorten the metabolic

disturbamice chime to lead! followimig treatment

in the acute stage, even when protectiomi

from leach appears to l)e ColTiplete. The

in-tellectumal outconie of the group of orally

treated patients was comparable to tile

group as a whole: three uninterrupted

re-coveries, two with slow recoveries showimig

temporary psychologic variatmomis, amic! tWo)

I 2 3 4 5 6 7 8 9 0 II 2 3 4 5 6 Il

MONTH AFTER CESSATtON OF LEAD EXPOSURE

Fmc. 4. l)tiration of copro1x)rphyrinuria in 6 patients treated contimuiotislv with e(lltlia111ih orally h)llowimig discharge fromn the 1U)51)it.ll (stippled i)ars) as coisipared to 10 I)lti(’m1ts who did not receive edathamil orally after

ohs-charge’ (solid liars). Both groups were carefully protected from re-exposure to lead and 1)0th grOIIp5 had l)een treated imi the hospital with intravenous

jjg% 25001

SQ.,.

0.5

LEAD POISONING

ERYTHROCYTE

PROTOPORPHYRI N

ERYTHROCYTE

COPROPORPHYRIN

URINE

COPROPORPHYRIN

EDATHAMIL LV.

G/ DAY

EDATHAMIL P.O

C/DAY

DAY I 2 3 4 5 6 7

I .5

;

--Ftc. 5.

8 9 0 II 2 3

NORMAL

Fm;s. 5, 6, 7. Comparative effect of oral versus intravenous

administra-tion of cclathaniil oh porphyrin nietabolismii in lead isomiing.

permanently retarded, one o)f whom was

probably retarded prior to lead poisoning.

A study of the relative effectiveness of

o)ral as compared to) intravenous or

intra-muscular administration of edathamil upon

the abnormal concentratio)ns of

protopor-phynmn amid copro)prophynin in the blood as

vell as on the urinary oumtpumt of

copropor-phiynin, was undertaken. Three children

were treated with edathamil intravenously

and then orally, in comparable doses, or

vice versa. As shown in Figures 5 to 7, only

slight and irregular improvement as regards

erythrocyte protoporphynin occurred with

either form of treatment, erythrocyte

copro-porphyrni was ummicertainly lowered!, urinary

o)uItpumt of co)proporphynin was diminished

to)Wardl O)r to normal levels by intravenous

edathamil, but this metabolic improvement

was not maintaimied reliably by sumbsequmemit

oral edathamil. #{176}

The difference betweemi the effects of

0 Quamititative porphyrin studies were domie for

us I))’ Dr. David Y-Y. Hsia.

echathamil on the erythocyte prophynimis andl

the urinary coproporphynin is confirmatory

of the notion that porphyrin metabolisni is

d!mstumrbed by lead! at several points, and that

ed!athamil d!O)C5 no)t, as noted

by

Ruibin,27

re-move lead effectively from the marrow.

Finally, imi one child, edathamil was given

orally by error while the gastroimitestinal

tract contained lead!, with disastrous resumlts.

Because this exl)enieliCe acIds to) the

kmiovl-edge of the physiology of ec!athamil, it is

reported in detail:

A 11Yi-year-olcl male was admitted to the

hospital because of irritability amid vomiting of

several weeks duration. He had walked at 14

months of age amid since that time had

cx-hibited pica for dirt, paint-flakes, wOO)dl and

putty. He was reported at the time of

aclmnis-sion to be umsitig a few single words, to feed

himself with a spoomi, amid to have no imiterest

iii Pictures. Iii the few weeks preceding

admis-sion he may have regressed a little

develop-memitally.

At the time of admnissiomi, he was a pale

hemo-NORMAL

ERYTHROCYTE

PROTOPORPHYRIN

ERYTHROCYTE

COPROPORPHYRIN

URINE

COPROPORPHYRIN

DAY

I

I

Fic. 6.

NORMAL

S Q

4500

4000

3500

3000 ERYTHROCYTE

2 500

PROTOPORPHYRIN 2000

I 500

I 000

500

Pg %

ERYTHROCYTE 5

0 COPROPORPHYRI N

5

59/24’

URINE I500

COPROPORPHYRIN I000

500 , -

-I I7 I8 I9 20 2I 22 2324

0.5

-37 38 39 40 4I 42 43 44

Fic. 7.

REVIEW ARTICLE 599

59

:::j1j-jji

25002000

500

pg.,. 5

0

5

Sq 24’

I500

I000 500

-9 0 II 12 3 4 5 6 7 8 9 2021

EDATHAMIL IV. I

C/DAY 0.5

I .5

EDATHAMIL P0 I

0./DAY 0.5

0#{149}

DAY

EDATHAMIL IV.

C/DAY

.5

EDATHAMIL P.O. I

C/DAY 0.5

ill for 5 days. His oleveloj)nient since this

epi-C SFTOTAL PR1TE5 MG% .

‘:

_

...______

- socle was niarkecllv retarded, and :3 ears lator

he \VdS imistittitiomiahizecl.

,oo

There can he little doubt that in this

in-stamice orally ac!mninisterecl ec!athamiiil

com-‘OAOO bimieci with leach salts in the gastrointestimial

tract amid caused their rapid ahsorptiomi into

I

the I)loodl stream. Though much of time leach

I

_At

wasleasec! excretedto the insoftthe tissuesurine, toemioughaugmnemitwas the

re-LRINARV LEAD G.”I24

pT o- , ,,

,#{149}

--

20 rnargimial emicephalopathv already present.

Simice this expeniemice, echathamil has not

2

been used orally for amiv

P0

EDATHAMLG/O*Y

I

END-RESULTS OF TREATMENT: The

over-2 all oimtcorne in 45 cases, 2 to) 4 ‘ears after

Iv (DATMILG.VDA tneatmnemit, is stated imi Table II. As imi other

__________________________________ series, the d!eatli rate is about as it always

CGMLSION$ & cOMA . .

nas i)eeml in leach poisomimmig. Two or more

Fm(;. 8. Clinical and cheniical cour5e of pmticmit years after treatniemit the imitellectual statums

given oral e(l.ltllaIiiil while i)OWel contained lead. of over half the chiildremi who co)uIldl be foummic! \‘as satisfact )rv. Of PIrtic1mlt1r

imiter-globin level was 5 gm, 100 ml, stippled ervth- est is the group o)f five child!reml who at first

rocvtes were seen in large miumbers in the presemiteci psvchologic irreeulanities o)f the

1)10001 smiiear, the imrimie showed a strongh’ posi type described by Bvers amid Lord, hut

tive test for conrooorphvrin amid a yellow me- . .

. . ..

‘

Who omi serial follow-imp study showed

grad-action for sugar in Benedmct s test. Roemitgeno- . . .

. ual resolumtlon of thie c!mfficultmes. How man

grains of the abclomemi showed much

raumo-Pit1e material scattered through the bowel, of the sevemi who still show’ such chifficumlties

and! o)f the long bomies showed condemisatiomi of time recover remains to) be seemi.

the hues of I)r\hiSi1itl calcificatiomi. The cere- Eight childiren tpi)eined! to 1)0’ grossly

brospimial flimicl s’aS clear, with a miormiial (1lmahi- amid permnanemitly retarded at the emid of the

tative test for sugar, a total Pr0)teili of 83 stumd!y amid these, tO)gethier with omie of the

mg 100 ml, amid no cells. four chilc!remi who d!fed, imicludech the five

Paint chips subsequemitlv obtaimied from the \vhi() were thoimglit pro)ixlblv retarded! prior

where he played contaimied 21sf leach. to) thi’ po)isonimig. Thus, fotmrchiilc!remi pp’a

It was planmieci to co)llect two 24-hour unimie

speciniens for lead cletermnination and during II

this period to evacuate his bowels, after which

(S trial of o)rah aclmiiinistration of edathiamil vas OUT(’O\IE 01” I3 (‘55E14 OF’ LE.sI) 1’OmsONmNu

. ‘J’IIF:.s’rEI) FlY Em).#{149}sTlr.s\1mm

to l)e macic. Through error he recemved a close

of 0.75 gin of eclathamiiil orally, viiemi he was

-put O)II the mnetabo)lism bed shortly after ad- 16

miiission, alidi a second dose 12 hours l:mter. Four

hours after the secondl close, he ral)i(llv lapsed ‘11

imito comiii, developed convulsiomis dmi(! time usumal 7

climiical sigmis O)f increased intracramiial 1)ressulre.

His chimiical course is depicted in Figure 8. 4

The essentials of this are: the umninarv excretiomi

of lead rose to the extraordinarily high level of 19

15 nig 24 hours; concomiiitamit vithi the onset

of conia, time level of protein in the

cerebro-sI)ilial fluid nearly (10111)1cc1; amid he was gravel’

45 600

1IIiI1mI)I(ie(l mmorllmal (I(V(10i)IIleflt

lemmipora ry psy(’iIoh)gi(’ irr(’gublrit ics

Nuss IlOrillOl

P(rsistent j)SV(I0)lOgi(’ irreglllarit i(’5

i’(’(’i)1(mIIiIl(i(’(I i)ead

3 a

S

3

SUMMARY

A review of the recent amid! 50)fliC o)ld!er

pertinent literature relative to lead

poisoml-ing in childhood is presented!.

Forty-five cases O)f lead poisoning fromii the

author’s experience are d!escnihed. All were

treated with intravenO)uS on intramimscular

administration of eclathamil c!uning the

acute stages.

Oral administration of ec!atharnil

pnc-ducecl no shortening of the prolomigec!

pe-nod O)f coproporphynmnunia following the

cessation of intravenO)uls use of ed!athianiil.

In the acumte stage, oral umse of echathamil

was less efficient thian intravenoums or

intra-muiscumlar ad!ministration in retunnimig the

aberrant porphyrin metah)olism toward

nor-ma!. The selective effect of intravenoums use

of ed!athamil on time urinary excretion of

coproporphyrmn as opposed to the relatively

slight effect on erythrocyte porphynins

con-firms the notion that lead interferes with

porphyrin mnetabohism at several

physiologi-- physiologi--

-

-

--

--

-

cally distinct points; amid that the

hiema-Feebleminded (3 PreviouslY) 6

Psychologic irregularities+peripheral Ileuritis I

Persistent psychologic irregularit ies 1

REVIEW ARTICLE 601

Bad outconme S

‘I’ABLE III

OuTcomE mx 17 (‘.s.sEs OF Ex(’Epu.sLol’STIIY

l)ead

idiotic (‘2previously)

Nomm-comnpetitive

ltapi(lly normal umemitally

‘Feinporary psy(llologie irregularities

Satisfactory (i)UtCOImle

Lost to study

to have been damaged grossly by the lead

poisoning.

Two special sumbgroups are worthy of

mention. Seventeen children were classified

as having encephalopathy and are described

in Table III : of these, four died and five

were finally idiotic (three probably

feeble-minded prior to illness); two, including the

5-months-old comatose infant, rapidly

be-came normal mentally following

treat-ment; and four more showed temporary

mental irregularities which have grac!umally

disappeared! in all; two childiren have been

lost to the study. These resumlts are definitely

encoumraging.

Eight children, largely owing to the

per-so)nahity characteristics of their parents,

were re-exposed to lead and are described

in Table IV: three of these were previously

retardedi mentally, and all eight had bad

re-suIts as far as intellectual attainmemit was

concerned. We agree with Chisolm and

Harrison1 that re-exposimre to leach after

treatment is c!isastrous, and that its

preven-tion is an important part of treatment of

lead poisoning.

These oven-all results compare favorably

TABLE IV

OUTcOSIE IN 8 CASES WT1I CoNTINuED EXPOSURE TO LEAD

‘rABLE \‘

OtTccmIE IX O (‘%SES TUEATED Pimmoit TO ITME OF

EDATHAMIL (BET NOT ‘I’HEATEI) WITh

1)IMEII-4 CAPROL) a I’IR)ItOt’GII l’ROTE(’TION I”I10I

5 ExposulmE TO LEAD

9 Imitellectually and enmotiommally iIItIICt 4

S1)eCimll j)SyC1II)logi(’ (lef(’etS vitlm later re(’overy

Intact 1 to 4 years after a(ute )oisoniI1g 6 6 (;ross psyCllOlOgi( defects

2 Persistent special )Sy(lmOlOgi(’ (lefe(’tS

17 Persistemmt intellectual (1I’f(’(ts ‘14 after poisoimimmg

I)iel 111 acute 1)111150’s

Lost to StU(ly (mntimimmgit is-1 ,nuved

away-‘2) 3

‘I’otal (IISCS

with similar resumlts in 20 cases o)f lead

poisoning seen from 1950 to 1952, treated

by a variety of methiO)d!s, hut all successfully

protected! from re-exposumne to lead. The

suits 2 to 4 years after the acimte episodic in

topoietic marrow is not freed of lead by

edathamil.

Edathamil given orally in the presence

of lead in the intestinal tract is a very

dan-gerous drug, and there is a hint that

admin-istration of even intravenoums edathamil may

promote lead absorption from the intestinal

tract and its transport to the brain.

There-fore, emptying the intestinal tract by

enemata may be an important preliminary

to treatment. Dehydration by severe

cathar-sis would be undesirable.

With adequmate treatment, half or more

of the victims of lead poisoning should be

returned to competitive life. Those

per-sistently damaged intellectually suffer from

acute encephalopathy and have often been

re-expo)sed to lead after treatment of the

acute disease.

REFERENCES

1. Melhins, R. B., and Jenkins, C. D. :

Epi-demiological and psychological study of

lead poisoning in children. J.A.M.A.,

158:15, 1955.

2. McLaughlin, M. C. : Lead poisoning in

children in New York City, 1950-1954;

an epidemiologic study. New York

J.

Med., 56:3711, 1956.

3. Greemiberg, M., and Jacobzimier, H. :

Ma-terial imi preparation.

4. Lead iii Modern Industry; Manufacture,

Applications and Properties of Lead,

Lead Alloys, amid Lead Compounds.

New York, Lead Industries Association,

1952.

5. Chisolm,

J. J.,

Jr., and Harrison, H. E.:

The exposure of childremi to lead.

PEDI-ATRICS, 18:943, 1956.

6. Milhican, F. K., Lourie, R. S., and Layman,

E. M. : Emotional factors in the etiology

and treatment of lead poisoning. Am.

J.

Dis. Child., 91:144, 1956.

7. Travers, E.

,

Rendel-Short,

J.

,

and Harvey,

C. C. : The Rotherham lead-poisoning

outbreak. Lancet, 2:113, 1956.

8. Biehusemi, F. C., and Pulaski, E.

J.

: Lead

poisoning after ingestion of a foreign

body retaimied in the stomach. New

England

J.

Med., 254:1179, 1956.

9. Rapoport, M., and Rubin, M. I. : Lead

poisomling; a clinical and experimental

study of the factors influencing the

sea-sonal incidence in children. Am.

J.

Dis.

Child., 61:245, 1941.

10.

de Mello, R. P. : Effect of light on urinary

coproporphvrin excretion in

lead-poi-soned rabbits. Proc. Soc. Exper. Biol. &

Med., 76:823, 1951.

11. Aub,

J.

C., Fairhahl, L. T., Minot, A. S.,

and Rezmiikoff, P. : Lead poisoning.

Medicine, 4: 1, 1925.

12. Kehoe, R. A., Thamann, F., and Cholak,

J.

: Lead absorption amid excretion in

re-lation to the diagnosis of lead poisoning.

J.

Indust. Hvg., 15:320, 1933.

13. Bessman, S. P., amid Layne, E. C. :

Distribim-tion of lead in blood as effected

by

edathamil calcium-disodium. Am.

J.

Dis.

Child., 89:292, 1955.

14. Tanis, A. L. : Lead poisoning in children;

including nine cases treated with

eda-thamil calcium-disodiumm. Am.

J.

Dis.

Child., 89:325, 1955.

15. Robinson, s-I.

J.,

Karpinski, F. E., and

Bnieger, H. : The concentratiomi of lead

imi plasma, whole blood and erythrocvtes

of infants amid children. PEDIATRICS, 21:

793, 1958.

16. Chisolm,

J. J.,

Jr., and Harrisomi, H. E. :The

treatment of acute lead encephalopathy

in children. PEDIATRICS, 19:2, 1957.

17. Bradley,

J.

E., Powell, A. E., Niermamimi,

w.,

McGradv, K. R., and Kaplan, E.:

The incidence of abnormal blood levels

of lead in a metropohitami pediatric chimiic;

with observation of coproporphvrinuria

as a screemiimig test.

J.

Pediat., 49:1,

1956.

18. de Langen, C. D., amid ten Berg,

J.

A. G.:

Prophyrimi imi the urine as a first

svmp-tom of lead poisonimig. Acta med.

scan-dimiav., 130:37, 1948.

19. Maloof, C. C. : Role of porphnins in

occu-pational diseases. I. Significance of

co-proporphvnintmria in lead workers. Arch.

Indust. Hvg., 1:296, 1950.

20. Chisolm,

J. J.,

Jr., and Harrison, H. E.:

Quantitative urimiarv coproporphnimi

cx-cretion and its relation to) edathamil

cal-cium-disodium administration in

chil-dren with acute lead intoxication.

J.

Chin. Invest., 35:1131, 1956.

21. Hsia, D. Y., and Page, M. : Coproporphyrin

stumdies in children. I. Urimiarv

copropor-phynin excretion in miormal children.

Proc. Soc. Exper. Biol. & Med., 85:86,

1954.

22. Rubin, M. : In use of calcium

ethvlemiedi-aminetetraacetate in treating

heavy-metal poisomiing. Report of conference

held at Massachusetts General Hospital.

Arch. Indust. Hyg., 7: 142, 1953.