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### An Age-Specific Kinetic Model of Lead Metabolism in Humans Author(s): Richard W. Leggett
Source: Environmental Health Perspectives, Vol. 101, No. 7 (Dec., 1993), pp. 598-616 Published by: The National Institute of Environmental Health Sciences (NIEHS)
Stable URL: http://www.jstor.org/stable/3431645
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All use subject to JSTOR Terms and ConditionsThis work was initiated under the Radon Research Program, U. S. Department

of Energy,

Office of Health andEnvironmental

Research, undercontract DE-AC05-840R21400

with Martin

Marietta Energy

Systems, Inc. Completion

of the model was funded by the Office

of Radiation

and Indoor Air, U.S. Environmental Protection Agency, under Interagency

Agreement

DOE no. 1824-C148-A1,

contract DE-AC05-840R21400, with Martin Marietta Energy Systems, Inc. Received 20 July 1993; accepted

7 September 1993. Although considerable

progress has been made in recent years in reducing human
exposures to lead, the potential for high intake of this contaminant Stiu exists in millions of homes and in many occupational settings. Moreover, there is growing evidence that levels of lead intake considered . . r

nconsequentlal )ust a tew years ago can resultin subtle, adverse

health effects,particularlyin children. Consequently,there have been increased

efforts by healthprotection agencies

to develop credible,

versatile methodsfor relating

levels of lead in environmental

mediato levels in blood and tiSsuesof exposed

humans of all ages.In a parallel effort motivated largely by the Chernobyl nuclear accident, the International Commission on Radiological Protection (ICRP) is assembling a set of age-specific

biokinetic

models for calculating radiationdoses from environmentally important

radionuclides,

induding radioisotopes of lead. This paper describes a new age-specific

biokinetic

model for lead onginallydeveloped

for the ICRP but expanded to indude additional

features that areusefill for consideration

of leadas a chemical

toxin. The model is developed

within a generic, physiologically motivated frameworkdesigned tO address

a class of calciumlike

elements. This framework

provides a useful settingin wlwich

to synthesize

experimental, occupational, and environmental data on lead and exploit common physiological properties

of lead and the aLkaline

earthelements. The modular

design is intendedto allowresearchers

to modify

specificparameter valuesor model components to address special problems in lead toxicology or to

* * P * t s P mcorporate

new mtormatlon. ransport or lead betveen compartments is assumed

to follow linear, first-order

kinetics provided the concentration

in red blood cells remains below a nonlinear threshold level, but a nonlinear relation betwveen plasma lead and redblood cell leadis modeled for concentrations abovethat level. The model is shown to be consistent

with data on human subjects exposed to lead under a variety of experimental

and naturalconditions. Key words: age-specific

metabolism,

biokinetics, kinetic model, lead. Environ

Hcalth Perspea 101:598 616(1993) Despite an overall decrease in humanexposure to lead in recent years (1-4), the potential for high intake

of this contaminant still exists in millions

of homes and in
many occupational settings. Moreover, there is growing

evidence that levels of lead intake considered

inconsequential

just a few years ago can result

in a variety

of subtle, adverse

health effects in the absence

of overt intoxication

(g7). Lead

poses a particularly great threat to young children, who have elevated contact with lead in dust, soil, and paint,elevatedgastrointestinal absorption

of lead,elevated

turnover of bone lead into blood, and incompletely developed organs anddefense

mechanisms. The growing awareness

of the health threat posed by lead has stimulated increased efforts tO develop

a detailedcharacterization of the biological

behavior of lead in humansof all ages. Several biokinetic modelsfor lead have now been published (8-20). Most of these were derived as
curve fits to limited data from controlled metabolic

studieson adult humanvolunteers or laboratoryanimals at different stages of life. In some cases

an attempt

has been made to improveupon such exposure-specific characterizations of lead metabolism

by synthesizing

data from a variety of exposure

conditions (18,12 or introducing

greater physiological

realism into the modeling

process (15,20. In an effort motivated

largely by the Chernobyl nuclear accident, the International Commission on Radiological Protection(ICRP) is assembling a set of age-specific

biokinetic

models for environmentally important

radioelements

(21,22. To this point,models

for bone-seeking

elements havebeen developed within one of two generic

model structures.

One of these applies to the "bone-surface-seeking" ele-

*

. . . . ments, lnc uclng p utonlum, amerlclum, neptunium,

and thorium(23). The other applies to the "bone-volume-seeking" or "calciumlike"

elements, including strontium, barium,

radium, and lead. Each of these model frameworks

represents a workable compromise

between biological

realism and practical

considerations

regarding the amount and quality of information available to determine

parameter

values. The generic

structure for the calciumlike 

### elements provides a useful setting in which to synthesize

experimental,

occupational, and environmental

data on lead and to exploit common physiological

properties of lead and the alkaline earth elements. The purposes

of this paperare to explain the conceptual

basis of the lead model as developed

for the ICRPand expand that model to include features that

areuseful for consideration

of leadas a chemical toxin but thatare

unimportant for consideration

of lead as a radiological toxin. In contrast

o the version

of this model developed for the ICRP,

the expanded version includes a relatively

detailed description ofcirculating

lead, a concentration-dependent

transfer rate intored blood cells (provided

the leadconcentration in red

blood cells exceeds a specified threshold level), andconsideration

of the brain as a separate compartment.

BriefOvennew

of the Model The model

describes the time-dependent distribution

and excretion of lead that has been injected or absorbed

into blood. This systemic model may be used in conjunction with any model describing thetranslocation of lead from the respiratory

or gastrointestinal

tract into blood.

The respiratory and gastrointestinal

models used in the present paper to evaluate humanexposure data or to compare

model predictions with observations

of the fate of inhaled or ingested lead are described in the appendix. A schematic

diagram of the compartmentsused in the systemic modeland directions of movement

of lead among these compartments

is given in Figure 1.A

more detailed schematic diagram ofthecirculation, i.e., the model

forlead in blood and rapidly exchanging extravascular

fluids,

. . . . 1S S.

### lown sn qlgure w. Transport of leadbetween

compartments is assumed

to follow first-order kinetics provided the concentration

in red blood cells (RBCs) stays below a nonlinear threshold concentration.

When the concentration in RBCs exceeds that threshold, the transfer

rate from diffusible plasma to RBCs is assumed

to decrease

as the concentration in RBCs increases. At the same time, the deposition

fractions in other compartments

are increased due tO 

### decreased

598 Environmental Health Perspectives 

# ^ 

# Research Advanc

An Age-specific Kinetic Model of Lead Metabolism in Humans

Richard W. Leggeff
Health Sciences Research Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 USA

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC All use subject to JSTOR Terms and ConditionsResearch Advances @ Kinetic model for lead in humans

Flgure 2. Model of the circulation. Diffusible

plasma is viewed as the central feeding compartment and extravascular fluids (EVF} are treated as a satellite compartment Leadthat moves between plasma and retention

sites in tissues is treated, in effect, as if it passed instantaneously through the EVF.

transfer rates (per day) between

compartments because software packzges for implementing compartmental models usually require transfer rates as input.Most of the derived transfer rates are secondary

values, however, calculated

from selected

removal half-times and deposition

fractions. The term adeposition

fraction" as used here refers

tO instantaneous

fractional

OUtflow from the diffusible

plasmacompartment.Forexample,

a deposition

fraction of 0.24 is assigned

tO RBCS. This means

that 24% of the leadatoms

leaving plasma in a short time (seconds) are assigned to the RBCs compartment.

Since the total transfer ratefrom diffusible

plasma to all destinations combined

is estimated

as 2000/day, the transfer

ratefrom diffusible

plasma to RBCs is 0.24 x (2000/day)

= 480/day.

The

useof deposition

fractions provides one way of introducing

consideration

of material

balance and competitionbetween compartments into the selection

of parameter

values. This also provides a convenient way to relate model parameters

to data on the early distribution

of tracer lead. In the present model, a deposition

fraction, F, for a compartmentother than the rapid turnover compartment,

EVF (which is assumed

to equilibrate

with diffusible

plasma within a few minutes after injection of lead into blood) indicates that the compartment accumulates

roughly 2 x Fx 100%

of the initial input to blood during

the first hour

or so after

injection. This is because

compartment EVFis assigned

a deposition

fraction of 0.5 and thus receives about halfof the injected

amount within minutes.

This initial inflow into EVFrapidly

redistributes to the othercompartments, virtuallydoubling the contents

of those compartments

over a short time. Figure 1. Compartments

and paths of movement

in the biokinetic

model for lead. The systemic model may be used in conjunction

with any model of absorption from the lungs or gastrointestinal tract The ZplasmaEVFn box, including

RBCs, represents

the modelof the circulation, which is shown in more detailin hgure 2.



### competition

fromthe RBCs,

but firstorder transport between allothercompartments is assumed

to be maintained

at all levels of exposure.

A nonlinear

threshold concentration

of 60 pg/dl RBC (corresponding to a blood lead concentration

of about 25 pg/dl) is assigned. Transfer rates between compartments

are given in Table 1 for thesixage groups considered in Publication

56 of the International Commission

on Radiological Protection (21,22. Transfer

rates forages intermediate

to those addressed in Table 1

are obtained by interpolating

linearly with age between the listed rates. For example, a transfer rate for age 4 years is calculated

as 0.25 times

the rate given for age 1 year plus0.75 times

the rate given for age 5 years. Changes with age in the biokinetics oflead during adulthood are notaddressed here, but variation

with adult

agein the rate of boneturnover,

in particular,

can easily be induded

in the model

if desired (23,24. Several software packages are available for solvingthe type of compartmental model described here. A particularly

elementary and efficient method of solution developed at this laboratory is described

in

a recent paper (2.2. Definitions 

### The "removal

half-time" from a compartment refers here to thebiological

half-time that one would observe, theoretically,

ifOUt

### flow from that compartment

continued while feeds from all other compartments

were stopped. The removal

half-time is shorter than the apparent

half-time in the presence of recyding.

For example, with the model structure used here, the estimated removal half-time from RBCs to diffusible plasma is S days, but the half-time in RBCs that is apparent to theoutside

observer is a fewweeks because the RBCs continually take up lead that has been released to plasma from bone, soft tissues, and RBCs. The term "transfer rate" as used here indicates fractional transfer perunittime from one compartment

to another.

(Note that thetransfer

rates in this model are not actually rate "constants"

because in many
cases they change with age and hence time.) The "total transfer rate" from a compartment refers to the sum oftransfer rates from that compartment

to all destinations.

For example, the total transfer ate fromdiffusible plasma to allother

compartments

is estimated as 2000/day,

which corresponds to a removal

half-time from diffusibleplasma ofIn(2)/(2000/day)

= 0.00035 day = 0.5 min. Parameter

values are expressed

as

Volume 101, Number 7, December 1993 599

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All use subject to JSTOR Terms and ConditionsTable 1. Age-specific transfer rates (per day} for the model indicated in Figuresl and 2

225years

1000.0 480.0 0.800 30.00 12.000 88.96 71.0 80.00 40.00 0.400 177.5

10.00 2.000 0.300 7.000 0.1390 333.3 0.139 0.50 0.50 0.50 0.50 0.0185 0.0185 0.00462 0.00462 2 0.0000822 6 0.000493 0.0312 0.0312 0.00693

0.00190 0.139

0.00190 2.079 0.00416 0.00277 0.00038 0.00095 F100 days 1 year

aTransfer

rates for ages intermediate to those addressed in Table 1 are obtained by interpolating linearly with age between the listed rates. For example, a transfer rate for age 4 years is calculated as 0.25times the rate given for age 1 year plus 0.75bmes the rate given for age S years. bPlasma-D

and plasma-B are diffusible and boundplasma compartments; trab and cort indicatetrabecular and cortical bone; surf and vol indicate bone surface and volume, and exch and nonexch indicate exchangeable and nonexchangeable bone. CFor most purposes, it suffices to assume instantaneous transfer fromurinary

bladder to urine. dThere is also assumed transferfrom the small intestine back to diffusible plasma.The assigned rate depends on the choice of a gastrointestinal tract model {see appendix}.

Research Advances } Leggett



### to the extravascular spaces (27,28,31).

A reasonable

estimate of the total transfer rate from diffusible plasma may be about 1.S 1.4/min. After conversion

of units and rounding, the total

removal rate from diffusible plasma to all destinations

is set at2000/day. As explained

in a previous

section, this value is used to 

### calculate transfer rates from diffusible plasma to various compartments. Basis for representing

RBCs as a single compartment.



### The RBCs have a highaffinity 

### for lead

andcontain

nearly all of the blood lead(BPb)

under most conditions. The blood concentration

increasesapproximately linearly with intake

at relatively low levels of intake but increases

more slowly with highlevels

of intake (17,18, 35). It has been found that thefraction

of BPbassociated

with plasma

increases at blood lead concentrations

substantially exceeding 25 pg/dl, and that there is also a nonlinear elation between lead in blood and that in urine, bone, and other tissues and fluids at suchlevels

(17,36L38).

As discussed later, such nonlinear behavior of lead at high levels

of intake may result largely from a reduced rate of flowfrom plasma into RBCs

as certain lead-binding components

of these cells becomesaturatE gWtW :



### , }r j.i,F ,1 0 , $ tlig L 9 $ > ' -' K < ---' < 4 !

Pathwayb
Plasma-D

to EVF Plasma-D

to RBCs Plasma-D

to Plasma-B Plasma-D

to Urinary

bladderC Plasma-D

to Small intestined Plasma-D

to Trab surf Plasma-D

to Cort surf Plasma-D

to Liver 1 Plasma-D

to Urinary

path Plasma-D

to Other kidney Plasma-D

to STO Plasma-D

to ST1 Plasma-D

to ST2 Plasma-D

to Brain Plasma-D

to Sweat RBCs to Plasma-D EVF to Plasma-D Plasma-B

to Plasma-D Cort surf to Plasma-D Trab surf to Plasma-D Cort surf to Exch vol Trab surf to Exch vol Cort exch vol to Surf Trab exch vol to Surf Cort exch vol to Nonexch vol Trab exch vol to Nonexch vol Cort nonexch vol to Plasma-D Trab nonexch vol to Plasma-D Liver 1 to Plasma-D Liver 1 to Small intestine Liver 1 to Liver 2 Liver 2 to Plasma-D Urinary pathto Urinary

bladder Other kidney to Plasma-D STO to Plasma-D ST1 to Plasma-D ST1 to Exoreta ST2 to Plasma-D Brain to Plasma-D 5 years

1000.0 425.1 0.709 26.57 10.629 56.83 199.2 70.86 35.43 0.354 148.4 17.71 1.771 0.266 6.200 0.2770 333.3 0.139 0.65 0.65 0.35 0.35 0.0185 0.0185 0.00462 0.00462 0.00154 0.00181 0.0312 0.0312 0.00693 0.00693 0.139 0.00693 2.079 0.00416 0.00277 0.00038 0.00095 10 years

1000.0 366.9 0.611 22.93 9.171 89.50 268.5 61.14 30.57 0.306 128.0 15.29 1.529 0.229 5.350 0.1390 333.3 0.139 0.65 0.65 0.35 0.35 0.0185 0.0185 0.00462 0.00462 0.00089 0.00132 0.0312 0.0312 0.00693

0.00190 0.139

0.00190 2.079 0.00416 0.00277 0.00038 0.00095 15 years

1000.0 300.6 0.501 18.79 7.514 132.25 341.8 50.10 25.05 0.250 104.9 12.52 1.252 0.188 4.383 0.1390 333.3 0.139 0.65 0.65 0.35 0.35 0.0185 0.0185 0.00462 0.00462 0.000512 0.00095{ 0.0312 0.0312 0.00693

0.00190 0.139

0.00190 2.079 0.00416 0.00277 0.00038 0.00095 1000.0 297.1 0.495 18.57 7.429 96.00 384.0 49.52 24.76 0.248 103.3 12.38 1.238 0.557 4.333 0.4620 333.3 0.139 0.65 0.65 0.35 0.35 0.0185 0.0185 0.00462 0.00462 0.00822 0.00822 0.0312 0.0312 0.00693 0.00693 0.139 0.00693 2.079 0.00416 0.00277 0.00038 0.00095 .o 406.9 0.678 25.43 10.171 57.60 230.4 67.81 33.90 0.339 141.5 16.95 1.695 0.763 5.933 0.4620 333.3 0.139 0.65 0.65 0.35 0.35 0.0185 0.0185 0.00462 0.00462 0.00288 0.00288 0.0312 0.0312 0.00693 0.00693 0.139 0.00693 2.079 0.00416 0.00277 0.00038

0.00095

1 |4 1 1 1000 Minutes after Injection



### rapidly to the extravascular

spaces and RBCs. A tiny fraction of thetotal

outflow from diffusible plasma is assigned to a protein-bound

compartment

of plasma that returns lead slowly to diffusible

plasma nd eventually

contains most of the plasma lead. Total transfer rate firom 

### dif siblu

plusma (to all destindtions). 

### Immediately after intravenous

injection of radiolead

into adulthumans,

activity disappears

from blood at a rate of about 1 /min (27,31-33), which

is similar to the rate determined

for radiocalcium

in human subjects (34). Theassigned

transfer rate of lead from diffusible plasma to all destinations shouldbe somewhat higher than 1/min, however,

to accountfor rapid uptake by RBCs (Fig. 3) aswell astransfer E 

# XDEI^kIl.Iu

¢1 1- iilKl 10 | f 89 s ffi BYI 1 gr



# B ht1 !%1t 1 gw ,| | m 1 >

,¢Ed _|s *

_

ar ' X ' M

t1 , S i

, , + - l w iw 5 lo loo looo

Minutes afterInhalation

Figure 3. Model prediction

{curves} and observations Icircles; representing data from Chamberlain et al. {27>1

of percent blood lead in plasma, as a function of time after administration of radiolead to adult humansubjects by intravenous injection or inhalation.

600 Environmental Health Perspectives 

### Model for Adults

Cirnllation Basis for twoplasma comparanents. 

### Soon after introduction

of a leadtracer

(radiolead)into blood plasma, the tracer is largely available for diffusion intoextravascular fluids andfiltration

by the kidneys (2a28). Under

steady-state

conditions, however, most of the plasma

leadapparently is bound

tO 

### proteins,

with a globulin having a particularly

high lead-binding capacity (29,30). Two plasma

compartments are needed to depict a gradual shift of a large portion ofplasma lead tO 

### nondiffusibleplasma

proteins(Fig. 2). Lead injected or absorbed

intoblood or returning to blood

from the extravascular

spaces is assigned to the diffusible

compartment within plasma,

fromwhich it transfers

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All use subject to JSTOR Terms and ConditionsResearch Advances @ Kinetic moclel for leacJ in hesmans



### ed.At least

one of these

components

may . P

. .



### present a movlng target ot sorts, ln that ltS formation may be induced

to some extent by prolonged

exposure to high levels

of lead (32. It appears,

therefore,

that a fairly detailedprocess

model of uptake

and retention of lead by RBCs would require several compartments,

with somebeing saturable and at least onehaving

an exposure-dependent

saturation level. At pre-

- Xo *_Xillil o

_ ;F..

. w-____>g:

ev ^ gliXS I ] ; wX

_ _iS]]: , _ _ _ R -

_

__ ' zw ct -- , r7G__

._ w

_ MS, .6,, C

_ | Ep

_ W

_ _ | I

_ ' .s1; ^ > ' es 7 - ' z - ||||Blw

_

W_-v S l

_ 

### m ws w5 _]X w i | S wo_ U _s S s I <r w www S W a g-_

*_

_ _1 r u Y - Er a! S M t3

C t = L i A;iq ;;ai s,;;;;a._ t s

_ - . . _ z = z S

9 w_ti=Xb I

_

- =-;ikDl1ll3llIIIHIE

_ s - D'-'--- ------ >--5X'-

. ....................... ,-L - ........................... ' s g l B w i W w i i B i W i | | 8 l l | l

05 1 10 100 1000

Minutes atterInjection

Figure4. Model predictions (curve) and observations lcircles; representing data from Chamberlain et al. {27)1

of the blood content of radiolead as a function of time after intravenous injection into adulthuman

subjects.

z | | | | S

. l

- I | I I | g11111 I I | !1|111

_ X0 11 a | E #_w s sl_

Q _ggR

_ iKw_ ,,^ _t==_111tff ^

__|_w_w3w_w_

= w___¢" i }__

* __E __|__ * __g__5g2WI

= Slcw Illit=!l | ff_Ww O ____! | l__

._ ____l | 1|_

_ ^e

_w

_ _ _ _ _ W _SS: B_S

O - --l

__ _-___ _____*___ @ @_|slllll@_la 

### ___e___a_ a _X11_|1__GgE 1111__X_X_

e _|S1 _9gS

n

_ 11 __i_|

_ _BiL1L_}L _0 10 C E uJ_F S__ 3gB_ _-_!lEll

_ _ _

R _R | W li -l

_s_3s_|_|_gw__ O _3|1- W-s

_ _ _

O | 16 24 w Z Z 56 64 n " Hours a*0r End ot Inhalation

Figure5. Model predictions (curve) and observations lcircles; representing data from Hursh et al. (42>] of buildup

of radiolead

in red blood cells as a function of time after inhalation by adult human
subiects 

### sent, there is not sufficient

quantitative information

to derive transfer rates for multiple compartments

within RBCs. In thismodel

the RBCs are represented

as a single compartment

in exchange

withdiffusible plasma, but nonlinear

kinetics is imposed at relatively

highconcentrations oflead in RBCs. That is, above a threshold concentration

flead in RBCs, the transfer rate from plasma to RBCs is assumed

to decrease as the concentration

of leadin RBCs increases. Tranger ates benveen dif sible pl=-

maand RBG. A minimum

blood content of about one-third of theinjected

amount is reached

within 2-3 min (Fig. 4), at which timeroughly

three-fourths

of BPb resides in RBCs (Fig. 3). The RBC content then increases

over a period of hours as mostof the systemically

distributed

lead returns to plasma (31,40,41).By 1 day after administration

of radiolead

to adult humans, blood typically contains 55-60% ofthe injected orabsorbed

amount (Figs. 4 and 5) 27,28,31,32,41-45).

Over thenext several weeks, lead is lost from blood with

a net half-time on the order of 15-20 days (Fig. 6) (9,27,28,32,46,4X.

As indicated in Figure 7, longer net half-times

andsizable intersubject

variability are apparent at times remote

fromexposure,

when the blood content may be determizned

asmuch by therate of feedback

from bone and soft tissues as bythe rate ofloss from RBCs.

10_||__|l

### Available data on retention

of tracer leadin bloodof human

subjects can be reproduced

reasonably

well by assuming that the RBCs 

### receive about a fourth ofthe lead atoms leaving diffusible plasma (more precisely, a deposition

fraction of 0.24 is assigned) and return lead to diffusible

plasma with a removal

half-time of 5 days. Thus,for low concentrations of leadin RBCs, 

### the transfer

ratefromdiffusible plasma to RBCs is 

### 0.24 x (2000/day) = 480/day. Asdescribed

later, thedeposition fraction for RBCs is 

### assumed

to decrease when the concentration

of lead in the RBCs 

### exceeds 60 1lg/dl RBC,

### which

corresponds to about 25 1lg/dl blood. TransJ2er rates between diJ*sible and boundpl4lsma

The protein-bound

fraction ofplasma lead is notknown,

but it appears to beconsiderably

larger than the diffilsible fraction under steady-state

conditions (26,29,30,37,48).

After parameter values for diffusible plasma nd RBCs 

### are set,reasonable stimates of the transfer

rate from diffusible plasma to protein-bound

plasma and of the removal half-time fromproteinbound plasma lead can be inferred

from data on 1) the time-dependent

division of radiolead between RBCs and plasma,

2) the steady-state

division of lead between RBCs andplasma,

and3) the ultrafilterable fraction ofplasma lead. Data on healthy human subjectsreceiving radiolead

by injection

or inhalation

6_ § " 

### _om rm2 ffi 

### SubjK B 0 [ wi3x9z5ffi>s g z | |
. ..... . |

> l_-| u--15 et

- _0 s E | D e = -Yf

; __=1"

cs

___ _ t e____ 

### - 3 =z__ a

____ __FW__

__ X -

___ 

### o 2 y E E 

### i ^

_ " 

### - | t

_ e Wk=]5SYt i i_ _, 

### ! W F

tn n ' - ' r er= ! I | 4, _-_ . s L o o

o
o

-

O !R1 100 150 200 250 300

Days atterBeginning

of Intake 50 100 150 2|0 Days aft0r Beginning

of Intake

o ul

.= 11



### a z

.> I

|

o o

- g

iL 

# a

0 2 4 6 8 10 12 14 16

Davs after Injection O 50 1W 150 2W 250 Davs afterBeginning

of Intake Days afterBeginning

of Intake

Figure 6. Model predictions{curve} and observations vertical lines; indicating range of values reported in Chamberlain et al. (27)1

of decline of lead content of blood as a function of time after injection of radiolead into adult human subjects. Predictionsand observations have been normalized to 100%

at 2.5 days. Figure 7. Model predictions

{curves} and observations [circles; representing data from Rabinowitz

et al. {9>] of lead content of blood of adulthuman subjects as a functionof time after beginning of controlled ingestion of an isotope of lead. Ingestionperiodsfor subjects A, B, and D were 104, 124,and 83 days, respectively;

subject E ingested the lead tracer for 8 days and again on days 42-51 afterthe initial intake. The gastrointestinal

absorption

fractions assuwed for subjects A, B, D, and Ewere 0.10,0.07,0.12, and 0.09, respectively, as derivedby Rabinowitz and co-workers (99

and adjusted by Chamberlain et al. (27).

Volume 101, Number7, December 1993 601

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All use subject to JSTOR Terms and ConditionsResearch Advances @ Leggett



### indicate that the RBCs contain 95-99% of theblood content of radiolead

at 0.5-1 hr after injection (31,33), more than 99% at 3 hrafter injection (31), more than 99.5% at 10 hr or more

after injection or inhalation (27), and about 99.8% at 50-100hr after injection (20). Experimental

determinations of the time-dependent

division of lead between RBCs and plasma in human subjects are shown in Figure 3 (275. Such findings for humans are reasonablyconsistent withmodern

data on laboratory

animals. For example,

morethan 99% of 2l0Pb in blood was associated with RBCs by 1 hr after

injection of this isotot)e into beagles (49); about99.8%of 2ltPb in blood was found in RBCs of adultmonkeys at 96 hr after

oral intake of thisisotope (50);andnearly

99.8% of 2l0Pb in blood was associated with RBCs by 1 day after injection into rabbits

(51). 

### In rats, plasma maycontain

as much as 2% of BPb, even atlow blood lead levels (20,5X. 

### The division

of lead between

RBCs and plasma ofchronically

exposed humans

or laboratory

animals has not been clearly established,

mainly because of thedifficulty in measuring

the typically

low concentration in plasma and the possibility

of cross-contamination

from RBCs (27,53). 

### Another complicating

factor is that (asdiscussed later) there is a nonlinear

relationshipbetween

the plasma

lead andblood lead concentrations,

at least when the latter greatly exceeds 25 pg/dl (17,18, 

### 3g38). According

to the ICRP (54),plasma lead accounts for about 10% of blood lead at equilibrium,

butmore recentestimates arein better

agreement

with the lower percentages

suggested by relatively short-term studies with radiolead. Data of Cavalleri et al. (5 

### and

deSilva (53) 

### indicate that plasma

may containroughly 1-2%of blood

lead for a widerange

of exposure levels. Measurements

of Everson and Patterson

(56;) suggest that plasma contained onlyabout

0.01% of BPb in a typically exposed person and about 0.15% in a person

with a high exposure. Manton and Cook (37) estimated that plasmacontains roughly 0.2% of BPb at anequilibrium blood lead concentration

of 10 pg/dl and as much as 2%at a concentration

of 100 pg/dl. Measurements

of Minoia and co-workers (57) on a large number of subjects with no occupational

exposuresindicate that plasma

may containroughly 0.1% of BPb. The present

model is designed to yield an equilibrium

plasma lead content of 0.2% of BPb forlow levels

of lead intake (but higher percentages

forelevated intakes), since this value is suggested by studies on humans

administered

radiolead and is reasonably

consistent with recentmeasurements

of stablelead in humans. Results of renal clearance studies on dogs receiving either a single injection or continuous

infusion of radiolead

suggest a gradual decrease with time in the ultrafilterable portion of plasma lead (26). These results, together withrenal clearance data

on chronically

exposed human subjects (37,48), indicate

that the ultrafilterable portion of plasma lead during continuous intake may be in the range

5-30%, with perhaps 15% being typical. Transfer ates between diffusible and bound plasma lead were setfor agreement with 1) data

on the early

division of radiolead between plasma nd RBCs, 2) experimental determinations

of urinaryclearance ofplasma lead (discussed later), 3) the estimate that plasma lead represents 0.2% of BPb at equilibrium,

and 4) theestimate that 15% ofplasma lead is ultrafilterable

at equilibrium.

The deposition fraction in the bound plasma

compartment

is set at 0.0004, yielding a transfer rate of 0.0004

x (2000/day)

= 0.8/day from diffusible to bound plasma. Theassigned

removalhalftime from bound to diffusible

plasma is 5 days, which is of the same

order as the half-life ofplasma proteins (58). Basis for the EVF compartment.

After intravenous

injection of lead, the blood concentration

is rapidly reduced by transfer from plasma to other extracellular

fluids, but the simultaneous

transfer from plasma to RBCs reverses the gradientwithin a few minutes

andbrings

back a substantial portion of extravascular

leadto blood (28,31,40,41).

Compartment

EVF is used to model this rapid feedback oflead from extravascular

spaces. This compartment is assumed

to exchange

leadonly with diffusible

plasma. Lead thatmoves fromplasma

to extravascular

fluids to retention sites in tissues is treated as if it passed directly from plasma to thoseretention sites and thus, in effect, is regarded as passing instantaneously

through the EVF (Fig. 2). This treatment

of the EVF

as a satellite compartment

rather than a central feeding compartment

allows the user who is not interested

in the early

kinetics of lead to eliminate

the EVF compartment without altering transfer ates for other compartments. Tranefer rates benveen diffiusible plusma and EVF. Thedeposition

fraction for EVF is set at 0.5 to reproduce

the early rapid return of lead tO 

### plasma from theextravascular spaces. Thus, thetransfer

rate fromdiffusible plasma to EVF is 0.5 x (2000/day)

= 1000/day. The transfer rate from EVF back to diffusible

plasma is assumed to be onethird asgreat, or 333.3/day;

this is derived from thepostulate

that theEVFcompartment contains three times asmuch lead as diffusible plasma at equilibrium,

which is suggested bykinetic analysis ofplasmadisappearance

curves for isotopes of thealkaline earth elements. For example, Hart and Spencer (34) estimated

from measurements on humans

injected withradiocalcium that the volume

of the rapidly

exchanging extravascular

fluids is about 3 (2.4 4.5) times

thevolume

of the plasma pool. Similarly,

Harrison and co-workers (5Q) concluded from measurements

on an adult male subjectthat intravenously injected radioisotopes

of calcium,

strontium,barium,

and radium

were rapidly dispersed intoan extravascular

poolabout three to four times the size ofplasma.

Bone Similurgiies

benveen lead andthe alkaline earth elements in bone. It has beenrecognized for many years that lead follows the movement

of calcium

in the bodyto a large extent and that physiologic

regulators of calcium

metabolism

usually affect the behavior of lead in a qualitatively

similar fashion ( 6 64)

. A particularly

close resemblance

between these two elements has been observed

with regard

to their behavior in bone. It hasbeen

found that lead competes with calcium for deposition in bone and distributes similarly to calcium and other alkaline

earthelements among different bones and betweentrabecular and cortical bone structures (49,6S 62,6n. Bone

lead may remain moremobile than bone calcium for some time after deposition

(66,67), but data on humans and laboratory animals indicate thatlongterm skeletal distribution

and retention are similar for lead and the alkaline

earthelements (49,68-71).

In human cadavers, the lead concentration

wasclosely

related to the calcium

concentration

in bone biopsy samples, despite the nonuniform

distribution of lead

found in the skeleton

(72). Lead has been used frequently asa marker of bone growth and osteon formation, and

a close resemblance

in the patterns

of deposition of lead and calcium in forming osteons hasbeen demonstrated

(73-77). Lead is incorporated

into the crystalline structure ofbone, where it replaces calcium ions at some sites (78-81).Burial

of lead beneath surfaces in regions of boneformation hasbeen

observed, andthere is evidence that leadis eventually

distributed throughout

the bone volume (73-77, 82-86). Similarities

between lead and calcium

are also evident with regard

to bone cell metabolism.

A significant

fraction of cellularleadin boneis rapidly

exchangeable and is modulated

by the same

ions and hormones

that regulate

bone calcium metabolism

(87-8S). However, highconcentrations oflead in bone leads to damage to bone cells andinterference

withbone remodeling

(9Gt).

602 Environmental Health Perspectives

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All use subject to JSTOR Terms and ConditionsResearch Advances h Kinetic model for lead in humans



### Structure of thebone

model. Based on the qualitatively

similar behaviors of lead and the alkaline earth elements with regard to bone, a bone model structure originally developed for application

to the alkaline earth elements (22,91) is applied here to lead. As far as practical,

parameter values

are developed on the basis

of lead-specific data, but appeal

is made to the alkaline earth analogy wherever data on lead are lacking. Themodel

structure is an updated

version of the long-standing

alkaline earth model for adult humans described in ICRP 

### Publication

20 (92. This

new version has been adopted by the ICRP 

### for consideration ofthe age-specific biokinetics ofcalciumlike elements. As in the ICRP's 

### earlier

model (92)for alkaline earth elements: 1) bone is divided into four primary parts: corticalsurface, cortical volunle, trabecular surface, and trabecular volume; 2) the rapidlyexchangeable material in bone is assumed to reside

on bone surfaces, meaning endosteal and periosteal surfaces of cortical bone, surfaces of haversian

and Volkmann canals, surfaces ofresorption

cavities, and surfaces oftrabecular bone. Bone surfaces do not include the surfaces of lacunae or canaliculi

and should not be confused

with the surfaces

of the sub-microscopic

bone crystals; 3) themore slowly exchangeable

material in boneis assumed to reside in bone volume; 4) longterm loss from bone is associated

primarily with boneresorption.

In contrast

o the ICRP's earlier model for alkaline earthelements: 1) redeposition

of material removed from bone compartments

is treatedexplicitly and 2) material is assumed to beremoved from all bone compartments

by first-order processes. The ICRP's earlier alkaline earth model is a catenary

(non-recycling)

modelinvolving a power-function

component

that accounts for most of the biological removal from bone volume occurring from a few weeks to several months after injection (92. Thisintermediate-term

lossfrom bone is generally ascribed to "diffusion"

of material into osteons and/or ionic exchange ofa portion of the element in deep bone withshallowbone pools or plasma calcium and has beenincorporated

into somebiokinetic models for lead (15,20). Actually, the

.. . . . 

### processes glvlng rlse to lntermec

late-term loss from bone have notbeen clearlyestablished, either for lead or for the alkaline earth elements. For lead, much of the loss from bone occurring from a few days to a year or more after exposure might result in part from the bone diffusion processgenerally hypothesized

andin part

from other processes, such as turnover

of lead-binding components

of theorganic

matrix of bone (93) orgradual release of lead from cellular components

ofbone. Whatever the processes,

the existence of intermediate-term

loss of lead from boneis indicated

by data on laboratory animals injected with radiolead (15,20,49, 71,82,94). ASso, the hypothesis that a substantial portion of bone lead remains exchangeable

for some time after exposure is consistent

with data on persons

who have received chelation therapy afterexposure to lead (95), although it must be considered thathighconcentrations

of lead may have changed the kinetics

of lead in bone. In thepresent

model, cortical andtrabecular bone volume are each viewed as consisting of twopools,

referred

tO 

### as the exchangeable

andnonexchangeable

pools (Fig. 1). The exchangeable

bone volume pool is identified

withintermediate-term loss from bone, meaning loss not associated with rapid

exchange with plasma

or slow loss by bone resorption. Calciumlike elements moving from bonesurfaces

to bone volume

are assumed

to enterthe exchangeable

pool andto leave

thispool withan element-specific

half-time (a few weeks or months).

Part of the material leaving exchangeable

bone volume is assumed to return to rapidly exchanging bone surfaces andpart is assigned to the nonexchangeable

bone volume, from which it is assumed

to be removed

to plasma onlyby bone

resorption.

The rate of removal from nonexchangeable

onevolume is equated

with the rate of bone turnover andis independent

of the calciumlike lement considered. The parameter values assigned to exchangeable

bonevolume and bone surfaces

are assumed

to include any effects ofbone resorption. The assumptions

that 1) bone

lead is rapidly exchangeable

if and only if it resides on bone surfaces, 2) bone volume is in exchange

with bonesurfaces

and not plasma, and 3) alllead reaching bonevolume is initially available forexchange

are, at best, only partially accurate. Thetrilayered model of boneis intended

only to approximate

the net result

of the various processes involved in the time-dependent uptake and removal

of leadfrom

bone, using first-order kinetics and a minimal number of compartments.

This layered

. . *

. . . 

### structure

1S conslstent 

### Wlth

a qua ltatlve model proposed by Rabinowitz

(95), who suggested that not all bone

lead is equally exchangeable

withblood

but has varying degrees of accessibility

untilpenetrating the crystal surface, after which

it 

### becomes firmly buried and must await osteoclastic turnover. Rates of uptake and loss by bonesurfaces. The net rate

of exchange

between diffusible plasma andrapidly

exchanging regions ofbone (assumed to beat the

bone surfaces) and the amount

of lead initially retained

in bone can be inferred fromgenerally consistent data on healthy adult male humans (28), baboons

(82), andbeagles (49) injected

with radiolead.

These data indicate that the adult skeletonaccumulates about 10-1 5% of intravenously injected leadwithin a few hours.

This rapid uptake may be followed

by a decline in the bone

content over the first day or two after injection and then a gradual increase overa period

of weeks as lead returns from RBCs and soft tissues to plasma and accumulates

in regions of bone with slower loss. By34 weeks

afterinjection, bonecontains

roughly 25% of the administered

amount (Fig. 8). These data

can be reproduced

reasonably well if it is assumed that1) the deposition fraction on all bonesurfaces

is 0.08. (Derivation

of transfer rates from diffusible plasma to the individual

bone surface

compartments requires additional information,

discussed below, on the initial division of lead between trabecular and cortical bone); 2) leadis removed

from each bonesurface compartment

at a rate of 1/day, with half of theremoved

lead returning to diffusible plasma nd half migrating to sites in bone with longer retention (exchangeable

bone volume). Thus, the transfer

rate fromtrabecular or cortical

bone surface

to diffusible plasma is 0.5/day, and the transfer rate from trabecular or cortical bonesurfaceto the corresponding

exchangeable bone volume compartment

is also 0.5/day. Injection data on a variety

of animal species (60,62,82,96)indicate

that the concentration

of lead is initially

much higher in trabecular

bone than in cortical bone. McLean and co-workers (6X found that the concentration

of radioactive

lead in trabecular

bone of dogs was at least five times higher thanthat in cortical

bone

r . . . , S

. 

### soon atter lnjectlon. nls seems

conslstent withlimited

biopsy data on human sub-

. . . . 

### Jects lngestlng a eac lsotope

tracer over a period of months

(Table 2), whenit is considered

that the samples

of cortical bone were almost entirely bone tissue, and the trabecular

samples probably contained about twice as much soft material as bone tissue, by mass (M. Rabinowitz,

personal communication;

18). Since the biopsies

were taken more than 3 months after the beginning of exposure,

some redistribution ofbone lead is likely to have occurred. The initial division oflead betweentrabecular and cortical

boneappears

to be similar to thatof the alkaline

earthelements[compare,

for example,

results of McLean et al. (62) forlead

in dogs with results ofNorrdin and Arnold (65) forcalcium in dogs]. As assumed

earlier forthe alkaline earth elements (91,97), therate of transfer of lead from diffusible plasma to trabecular and cortical

bone surfaces

is

Volume 101, Number7, December 1993 603

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All use subject to JSTOR Terms and Conditionsexposed tO lead,summarized

in a latersection, are consistentwith the assumption thata relatively

small portion (on the order of 20%) of lead entering bone volume is retained over an extended period. The inferred pattern of translocation

of lead fromexchangeable

bone volume

is broadly similar to that described

earlier for radium (91). By analogy

with radium

it is assumed that the removal

half-time of lead from exchangeable

bone volume

is 30 days,

that 20% of lead leaving exchangeable bone volume moves to nonexchangeable bone volume, and that 80%returns tO bone surfaces. Thus, the transfer rate from the exchangeable

tO the nonexchangeable

bone volume compartment

of either trabecular

or cortical

bone is 0.2 x 0.693i(30 days) = 0.00462/day

and from exchangeable

bone volume to bone su&ce is 0.8 x 0.693/(30 days) = 0.0185/day. 

### Rates of loss from nonexchangeabk bone comparttnents.

Studies of beagles injected with radioisotopes

of lead, radium,

or strontium

indicatethat skeletal

retention is similar

for these elements,

particularly after a few weeks,

and that their rate of removal

from the skeletonafter a few months may be largely

controlled

by the rate of bone resorption

(49,71). As in an earliermodel for the alkaline earth elements (22,91), it is assumed that the rate of removal

of lead from nonexchangeable bone volume is the same as the rate of bone turnover

and that lead leavingnonexchangeable

bone volume enters

diffilsible plasma. The age-specificbone turnover rates given in Table 1 are those developed in an earlier

paper (97) and adopted

by the ICRP (21). Thesevalues

arebased on histomorphometric

measurements

on human subjects and studies

of retention

of certain bone-seeking

radionudides

in human

subjects. Most histomorphometricmeasurementsareon ribsand iliaccrest, but there

Table 2 Measurements and model predictionsof the concentration {p9/9} of lead in biopsied iliac bone from human subjects ingesting a lead isotope tracer over a periodof monthsa

Observed/this

model Subject A Subject B Bonetype dayll6 daylO5

Trabecular 0.075/0.097 0.045/0.060 Cortical 0.049/0.058 0.054/0.036

aDataare from Rabinowitz et al. (9>. The concentrations are expressed on a fresh-weight basis. The observations indicate considerably greater concentrations of lead in trabecular than cortical bone tissue at 105-116 days from the beginning

of
exposure because trabecular biopsy samples generally contain more soft material than bone tissue by mass. Model predictions are based on the assumption that the cortical samples represent 4000 9 of bone tissue and the trabecular samples represent 1000 9 of bone tissue plus 2000
g of soft material. Research Acivances a Leett

are also a few measurements for various long bones.

It is assumed

that there areno differences

in turnover

rates of cortical and trabecular bone early

in life but thatdifferences gradually

appear during childhood and eventually

grow tO about a factor of 6 in the mature

adult. Differences

with age in bone turnover

during adulthood

(23,24, 97) are not addressed

here. Several authors have attempted to identify a single,

long-term turnover ate of lead in the adult human skeleton. Estimates have beenbased

on animal studies, the rate of bone remodeling,

balance considerations regarding 2l0Pbor stable

lead, the dedine of BPb after

the end of occupational

exposure, and in vivo measurementsof the decline of 2l0Pb or stable lead in bone after elevated exposures (46;98-107). Estimates have ranged from about 0.007/year to about 0.1 5/year. Cohen and co-workers

(107) used in vivo measurements

over the skull and urinary excretion

measurements

to estimate the rate of decline of 2l0Pb (radiological T1/2 = 22.3 years)

in a subjea contaminated with this radionudide 33 years before the initial measurements in 1980. They estimated from in vivo measurements that the total-body content was 9.55 kBq in 1980 and 5.88 kBqin 1990. If exponential dedine is assumed,

these initial and final estimates would indicate a biological removal rate of 0.017/year.

If three

in vivo measurements

made between 1980 and 1990 are induded and a best exponential fit to the five measurements is derived,

a biological removal rateof only 0.007/year is obtained.If it is assumed that urinary excretion represents 55-60% of total excretion of lead at times remote from exposure (seethe section

on excretion),

the urinary excretion measurements

(taken in 1990) indicate

a biological

removal rate of 0.021-0.023/year.

The present

modelpredictsthat a total-body

burden of 9.55 kBq of 2l0Pb remaining after an acute intake 33 years earlier

would decline tO 5.15 kBq after10 more

years, and that the biological removal rate from the total body at 43 years wouldbe about

0.027/year

(if model predictions

for 42-44 years are approximated by a single

exponential

function). Christoffersson

and co-workers

(108) used in vivo X-ray

fluorescence

to measure the dedine of lead

in finger bonein former lead workers.

For eight subjects

followed for up to 5 years,

a biological

half-time of 6.7 (range

3-15) years

was estimated.

In a second group of six persons

followed from year 7 to year 13 after

finishing lead work,

a half-time

of 8.2 (range

2) years

was estimated.

There was generally

good agreementbetween

the estimated

dedine of lead in finger bone and the dedine in blood of these subjects(106,108). Basedon these 

# _ r - .@ (Semiffluanitative Data}

=

_ O ubs at 5 * B_ @_

0 5 10 15 2@ 25 311 35

Dap af"r Injection

Figure 8. Model predictions and observations of the lead content of the adult skeleton as a function of time after intravenous injection. The observations for humansare indirect estimates for subjects intravenously

injected with 203Pb,

derived by consideration of material balance, together with external measurements over the feet {28>. The data point

for beagles is from Uoyd et al. {49S, and data for baboons are from Cohenet al. {(.

assumed to be proportional tO the calcium addition rate of the givenbone type. Since there is roughly four times as much cortical bone as trabecular

bone by mass in the adult human (54), and the rate

of addition of calcium

per gram bone is on the order of five tO Six times higher in trabecular than cortical

bone as an average

over all adult ages (91,9iO,the rate of transfer of lead from diffusible

plasma

tO trabecular surfaces is estimated

to be 1.25 (5/4) times higher than that to cortical

surfaces in the adult. Since the deposition fraction for all bone surfaces

of the adult is estimated

as 0.08, the transfer

rate fromdiffusible

plasma to trabecular

bones&ces is

(1.25/2.25) x 0.08 x (2000/day) = 88.9/day

and the transfer

rate from diffusible plasma to cortical bones&ces is

(1.00/2.25) x 0.08 x (2000/day) = 71.1/day.



### Rates of loss from the exchangeabk bone volume compartrn4nts.

Parametervalues for the exchangeable bone volume compartments

are based on 1) data on retention of 210Pb

in whole bodies and bonesof baboons

(82) and beagles

(15,49, 94); 2) the fraction

of total-body

lead in bone of chronically

exposed humans;

3) apparent similarities between lead and radium with regard

to intermediate-

and long-term retention in bone; and 4) the assumption

that the transfer

rates to and from exchangeable

bone volume are the

same for trabecular

as for cortical bone. The data on baboons

and beagles

suggest that most of the peak content of lead in bone is removed

from the body within a 

### fewmonths.

Data on humans

chronically

604 Environmental Health Perspectives

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All use subject to JSTOR Terms and ConditionsResearch Advances 2 Kinetic model for lead in humans

dataand additional

measurements

of lead in bone biopsies (vertebrae), blood, and urine of presentor former lead workers, Skerfving et al. (106) concluded

that the skeletal ead pool is not kineticallyhomogeneous, that turnover

of lead is faster

in the mainly

trabecular vertebrae thanin the mainly compact finger bone, and that the aaverage over-all half-time is probably

5-10 years." Only broad comparisons between model predictions

and findings

of Christoffersson,

Skerfving,

and co-workers

can be made due to the paucity

of information

on the lead exposures

experienced

by the subjects. The model

does not predict

a single biological

half-time for bone after an extended elevated exposure; rather, the rate of loss fromthe total skeleton is predicted to decrease

gradually

as the fraction of bone lead in nonexchangeable cortical bone increases.

Also, the rate of decline depends somewhat on the pattern and duration of the exposure,

which affect

the distribution of bone lead at the end of exposure. For presumably

realisticoccupational exposurescenarios, the predicted dedine in total bone lead after the end of exposure corresponds

tO a half-time

on the order of 10-12 years

duringthe first few years after exposure and roughly

25 years at 25-30 years

after exposure.


### Liver: Model Seructure and Transfer Rates The liver andkidneys

are treated separately from other soft tissues because of their importance

as excretion

pathways for lead andbecause

they showsubstantially

higher concentrations

of lead than most soft tissues. Data on injectedlead in human subjects (263,baboons

(8X, and beagles

(42 indicate that the liver rapidly

accumulates 1>15% of systemic

lead and loses much of this within a few weeks.In chronically exposed adulthumans,

the livermay contain about 2-3% of total-body lead, and the blood-to-liver

lead concentration

ratio is about 0.2 (54,109-115). Part

of the loss of leadfromliver

can be accounted

for by biliary secretion into the gastrointestinal contents (9,114), but return

of a considerable portion of liver lead to blood must also be postulated

due to the limited

losses of lead in feces. Since the level of biliary secretion of metals varies considerably from one species

to another

(11iD,quantitativeinformation

on biliary

secretion of lead by laboratory

animals (particularly rodents) is of limited

value for present

purposes. In thismodel

the liver is viewed as con-

. . P SlStlllg 0t two 

### compartments. A compartmentwith relatively

high uptake

from plasma nd a relatively short removalhalftime (several

days) is needed to help reproduce the pattern

of uptake and decline

of leadobserved

in human subjects, baboons, and beagles

during the first fewweeks after intravenous

injection. An additional

liver compartment

with much smaller

uptake but with gradual

build-upof lead over a period of years is then needed

tO reproduce the blood-to-liver concentration ratio determined from data on chronically exposed human subjects. The two liver compartments

arereferred

tO as liver 1 and liver 2. Available data on hepatic uptake

and retention of leadin htumans

and laboratory animals and on biliary

secretion of lead in humarz can be reproduced

reasonably

well with this two-compartment modeland the following assumptions:

1) of lead leavingdiffusible plasma, 4% deposits

in liver1. Thus, the transfer

ratefrom diffusible

plasma to liver 1 is 0.04 x (2000/day)

= 80/day; 2) the removal half-time from liver 1 is 10 days.

Of lead learring liver 1, 10% moves to the longtermretention

compartment

(liver 2), 45% enters the contents

of the small

intestine via biliary secretion, and 45% returns

to diffusible plasma. Thus, the transfer

ate from liver 1 tO liver 2, for example, is 0.1 x 0.693/(10 days) = 0.00693/day.

Leadentering the contentsof the small intestine in liver bile is assumedto follow the same kinetics as ingested

lead (see appendix);

3) the removalhalf-time from liver 2 is 1 year. All lead leaving

liver2 is assumed tO return tO diffusible

plasma. Model predictions

are reasonably

consistent with data on chronically exposed adult humans indicating that the liver

may containroughly

2-3% of total-body

lead. Also, the model predicts a blood-to-liver lead concentration ratio of 0.2 for the chronically

exposed adult, in agreement with the data on adult humans. Model predictions

of the adult liver content of lead during the first several weeks after injection are compared

in Figure9 with data on human

subjects, baboons, andbeagles injected

with radiolead.

The observations for human subjects indicated in Figure 9 are only semiquantitativeestimates based on external measurements. The liver content in baboons

or beagles at 1-2 months

is expected

to provide

only a lower-bound

estimate for humans

because the lead contents in the total body and blood (and presumably

all compartments with relatively

high turnover

rates) decline faster in those animals than in humans (28,49,82.

Kidneys: Model Structure and TranslEr Rates 

### Results of studies on dogs and rodents indicate that the kidneys

may accumulate

as much as 15-20% of intravenously injected radiolead within the first1-2 hr, that the preponderance

of the deposited activity represents filtered lead, and that a substantial portion of the early

accumulation is reabsorbed

or lost in urine within a fewhours

(118-120. 

### In rats,

the kidneys contained roughly 10% oftheintravenously injected amount after 1 day but less than 2% after 9 days (8X. 

### In baboons

receiving radiolead byintravenous

injection, thekidneys contained roughly 4% of theadministered amount after 1 day, 0.6% after 30 days, and 0.1% after 60 days (82. 

### Comparison of thededine

of renal and hepatic activity over the first

tWO 

### months

in these baboons indicate a half-time in the kidneys that would be roughly

one-half of that in theliver, if each of these organs wereconsidered as a single compartment.

This agrees with estimates

of Mallon (13) for baboons exposed to lead by daily ingestion

over a period of a few months.

In dogs

. . 210

. . . 

### recelvlng Pb by lntravenous lnJectlon, the kidneys

contained about 0.5% of the administered

activity at 1 month

(49). In this model the kidneys are viewed as consisting of twocompartments,

onewith relatively high deposition but shortretention of leadand one with relatively low uptake but long retention. Thesecompartments are referred

tO 

### as the "urinary

path" (UP) and "other

kidney tissue" (OKT), respectively.

Both are assumed to receive lead from diffusibleplasma. Material removed from UP moves

to the urinary bladder contents, andthat removed from OKTreturns

to diffusible

plasma.Compartment UP is needed

to reproduce

an early rapid buildup andfairly fast (days) decline of lead in thekidneys

as indicated by data on laboratory

animals, as well as the early (2-week) pattern of decline of lead in urine as indicated by data on human subjects injected with radiolead. Compartment

OKTis needed

to reprozs S

* | f |

- | | |

.
- -Mosbl PileboZs
ZD --- H_"{Semi-quanitativeData) _ *!f W | 9 l 111 n

; _- I | | V * 1 ll 11E

* Ihl

_ IE " I

s= AR .= WH B I _E

__

a _[ ___W 3[__[__ _ _e- _X=

X 10-| _r @ _g g !

__ §§_t

___ @ __|f |R

_ _ __|_ |

at a

___ _|-_-__ ___||_|_ -| - - - | - | |-|-----| -

O 10 20 30 40 50 60 70

Dass aner Injection

Figure 9. Model predictions and observations of the lead content of the adult liver as a function of time after intravenous injection.The observation

curve for humans is based on external measurements on adult human subjects intravenously injected with 203Pb

{28). The data point for beagles is from Lloyd

et al. (49f,and data for baboons

are from Cohenet al. {82).

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### Brain: Model Structure

and Transfer Rates The brain is considered

explicitly in this model because ofits high sensitivity to lead

as a chemical

toxin. Lead

is distributed unevenly in the brain,

withthe distribution depending to some extent on the level ofexposure.

At low levels, the leadconcentration in different

regions of the human brain is significantly

correlated with the

. . . . . 

### potasslum concentratlon,

lnc ilcatlng t zat lead is mostly

accumulated

in cell-rich parts of the brain such asthe hippocampus (122-124. As 

### with other

types of cells, lead entering brain cells apparently is taken up rapidly by mitochondria,

accumulating predominantly

in those regions wherecalciumlocalizes

(8X. At very

high levels, lead gains access to neural tissue following breakdown

of the blood-brain

barrier (124. 

### In cases

of lead poisoning in young children, the lead concentration

of the brain becomes extremely high and may approach or even exceed that of the liver and kidney (125,126. 

### It appears,

therefore,

that a fairly detailed model of the behavior

of lead in the brain would require multiplecompartments and consideration

of nonlinear kinetics. Due to limitations

in kinetic data, however, thebrain is treated here as a singlecompartment

that exchanges leadslowly with diffusible plasma, and linear kinet-

. . lCS lS 

### assumec

. Data on baboons,

dogs,and rodents indicate that thebrain has lowuptake

but tenacious retention of lead (49,82,124. 

### In young adult female baboons intravenously injected with210Pb,

the brain contained about 0.04% of theadministered

lead at 1 day but continued

to accumulate

activity released by other organs, showing about 0.07% after 30 days and 0.08% after 60 days (82).In beaglesg

the brain contained 0.04% of injected

21 

### Pb at 1 month

after injection and <0.003% at3-4years. An assumed

deposition

fraction for brainof 0.00015 [corresponding to a transfer ratefromdiffusible

plasma to brain of 0.00015

x (2000/day)

= 0.3/day] anda removal

half-time of 2 years yield predictions

that are reasonably consistent with injection data for large laboratoryanimals andwith autopsy

data for occupationally as well asenvironmentally

exposed adult humans. The model predicts that the adult brain contains 0.04% of administered lead at 1 day and 0.13% at 60 days after injection and gradually increases to a peak content of0.15% at6 months.

Other Soft Tissues:

Model Structure and Transfer

Rates The remaining

soft tissues,

consisting of skeletal muscle, fat,skin, and a variety of small organs and tissues, represent most of duce blood-to-kidney

and liver-to-kidney lead concentration

ratiosobserved

in chronically exposed persons. No attempt

is made to quantify

separately the rates of glomerular

filtration, tubular absorption, and tubular secretion, all of which

apparently occur for lead (26,119,121). 

### Rather, movement of lead from diffusible plasma into the kidney compartments

and urinary bladder contents is described

only in terms ofthe net result ofthese three processes. Theparameter

values for theUP compartment of the kidneys were based largely

on the data for laboratory animalssummarized above butwere adjusted for consistency withtime-dependent

urinaryexcretion rates observed in human subjects acutely exposed to radiolead

(see the discussion of the parameter

values describing urinary excretion). No attempt

was made to reproduce

the rapid accumulation

and decline of lead in the kidneys

that occurs in the first hour ortwo after injection. It is assumed

that 2%of lead

leaving diffusible plasma deposits in the urinary path compartment,

UP,yielding

a transfer rate from diffusible plasma to UP of 0.02

x (2000/day)

= 40/day. Theremoval

halftime from UP to theurinary

bladdercontents is assumed to be 5 days,

corresponding to a transfer

rate of 0.693/(5

days) = 0.139/day. After the parameter

values forthe urinary path compartment

wereselected, those describing uptake and removal

by the OKT compartment

(which represents tenacious retention in the kidneys) were set for consistency

with estimated relative lead contents in liver and kidneys

of human subjects chronically

exposed to lead. That is, parameter

values for this compartment

were set to account

for the difference between the total kidney content and the content of the urinary

path compartment during chronic exposure. It is assumed

that the OKTcompartment receives 0.02% of lead leavingdiffusible plasma (amounting

to about 1% of thetotal deposition in thekidneys).

Thus, the transfer

rate from diffusible plasma to OKT is 0.0002x (2000/day)

= 0.4/day. The removal

half-time from OKT to diffusible plasma is assumed to be 1 year,

corresponding to a transfer

rate of 0.693/(365 days) = 0.0019/day. The model predicts that the kidneys of the adultwould contain

almost 5% of intravenously

injected lead after 1 day, almost 2% after 1 month, and almost 1% after 2 months. The model was designed to overestimate

observed kidney contents in baboons and beagles

at 1-2 months

because the content

of lead in blood and the total body decline faster in those animals than in humans. thebody's mass butonly a smallpercentageof its lead

content in the chronically exposed adult. Data on laboratory

animals administered

radiolead indicate that initial deposits of lead in skeletal

muscle and other massive soft tissues are largely cleared by 1 day after

administration

and that these tissues probably account for no more than 34% of the absorbed

amount after thattime (49,52, 82,94, 119, 12@

. 

### There

are indications, however, that small amounts

are tenaciously

retained in skeletal musde, aorta, and perhaps

other soft tissues (49,82). 

### In this model theother soft tissues are assumed to consist of three compartments, ST0, ST1,andST2, representing a wide range of turnover

ates. Thesecompartments are based primarily on kineticconsiderations

and cannot

be given precise anatomical definitions. Compartment

ST0 is assigned

a high turnover rate and, together with bonesurfaces, accounts for most of the feedback from extravascular

spaces to plasmaoccurring from about 30 min (when

compartment EVF is virtually

depleted) to a few days after acute intake. Based on the blood "reappearance"

urve for lead during the first dayandconsiderations

of massbalance ofthe deposition fractions in different organs, it is assumed

that ST0 receives almost 9% (precisely,

8.875% to achieve

mass balance of deposition

fractions) of leadleaving

diffusible plasma and loses lead to diffusible

plasma with a removal half-time of 8 hr. Thus,

the transfer

rate from diffusible plasma to ST0 is 0.08875 x (2000/day)

= 177.5/day

and from ST0to diffusible plasma is 0.693/(0.333

day) = 2.08/day. In beagles injected with 2l0Pb, softtissues other than liver, kidneys, andbrain contained about 3% of the injected amount at 28 days and less than 0.2% at 1100 days (49,94). Most of the other

soft tissue content at28 days was found in pelt. Inthis model, compartment

ST1 is used to depict such intermediate-term

loss (i.e., a few weeks or months)

from other softtissues and also serves asthe source of loss of leadfrom the bodyin substances

other thanurine,

feces, and sweat (e.g., hair, nails, and desquamated

skin). Thedeposition fraction

for ST1, the totalremoval half-time from ST1 to diffusible

plasma andexcreta,

andthe division

of outflow between diffusible plasma nd excreta were chosen for broad consistency

with data on intermediate-term

retention of lead in soft tissues of laboratory

animals anddata on the rate of lossof lead

in hair, nails, and skin of human subjects 

# (9?. It is assumed that ST1 receives 0.5% of lead leavingdiffusible plasma. The total removal half-time from ST1 is assumed to be 100days,

with

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### 60% of theoutflow

returning

to 

### diffusible plasma and40%

lost 

### in hair,

nails, and desquamated

skin. Thus, the transfer

rate from diffusible plasma to ST1 is 0.0()5

x (2000/day) = 10/day, thetransfer

rate from ST1 to diffusible

plasma is0.6x 0.693/(100 days) = 0.00416/day,

and the transfer

rate from ST1 to excreta

is 0.4 x 0.693/(100 days) = 0.00277/day. Compartment

ST2 represents

tenacious retention of a small amount of lead in soft tissues

andis used

to account

for most of the lead

in massive softtissues of chronically

exposed humans. To avoid a gross overestimate

of data for beagles injected with 210Pb,

it must be assumed thatno more

than 0.1% of the injected amount is deposited

in a soft-tissue

compartment with a retention

timeof years. Then,in order

for compartment

ST2 to gradually accumulate

the level of leadindicated by autopsy

data on chronically exposed humans, it must be assumed

that the removal

half-time from compartment ST2 is at least

5-10 years.

It is assumed here that compartment

ST2receives

0.1% of outflow

fromdiffusible

plasma and returns leadto diffusible

plasma with a removal half-time of 5 years. The transfer rate from diffusible plasma to ST2 is 0.001

x (2000/day)

= 2/day and thetransfer

rate from ST2 tO 

### diffusible plasma is 0.693/(1825

days) = 0.00038/day. The model predicts that the three other soft tissues, ST0, ST1, and ST2 combined, contain 6%of intravenously

injected lead at 1 day, 4% at 1 month,

and less than 1% at 3 years after injection. Aswith theliver andkidneys,

the model wasdesigned

to yield reasonable consistency

with the data

on chronically

exposed humans, and the injection data on baboons

and beagles were assumed to provide lower-bound

estimates for humans.



### Excretion: Model Structure and Transfer Rates Excretion of lead is divided into fourpathways: urinary excretion, fecal excretion, sweat, and all other

excretion pathways combined (mainly hair, nails, anddesquamated skin). It is assumed

that a portion of leadentering

the urinary

bladder passes directly from diffusible plasma to the urinary bladder

contents and the rest is released to thebladder

contents aftertemporary retention in the renal tubules(compartment UP). Lead in feces is assumed to originate from two sources:

biliarysecretion from the liver contents (liver 1) into the contents

of the small

intestine and secretion from all other sources (assumed to be diffusible

plasma in this model) into the contents

of the small

intestine. It is assumed thatthe absorption

fraction for lead entering the small intestine in liver ; g g | | | | | | | E | lX 1 raRm 

### s | | 0 | g | | | | | | X |

. X | | | X X X X | | | 'r) =1

- | i | E | E E E g | | W @ e p . p § R w w w 1 w * v {t RQ 4 X, N

. | S | S g S , gX X -' g.

1D DDl' ._ _E= =EE.

. _ =E =S = n _= n_ =g

.= EEEEXX @ @@@@|= ||= |

e ==|== = W t1 = Q QQQX
X X8 =

- w____ @s X = =g

" Xi = O

_ m_;

_ _ ssag BB sa6_s

_ a

a 0 5 10 15 20 25 3D 35 40 45 50 at Hours

after Intake ; 06 = =|= =

||||||l INHAL^noN |

_ as B{a)X-7 @ @_=gES

ffi 1|1_ v * {3z)"4 S

_}=S *s Elt

_ 0

_ _# v xev {h-1 X

*- _ES_=El=w

n --=

_E_

_ *- t3 _=

s___}} }g X __X_X_8X8| =E

@ t_| = =EE=|_

@ Q2l- ' L== _S|=| = X 1 11|_

- _-_|_ =ffi_ffi_E =

= Q1= = .0

_ =______r_

*" _$ffi X 10=.

a 0 S 10 15 20 25 30 35 40 45 S0 at Hours

atter Intake

_ t7 = ;;

s 0.6 Sg; g INGEmON g ; =||=|8|X o U7)dS i 5wX * {a"4,h W @ W_ S_= - . *^ LJ = l = =E ,-,LJ -§1 X , *,,,,

- ; {ingesting Pb W = a-=_= '-= 1-2 hr later) i

= =_ = S

*

_ = = SS 2aqP5 KZYPS

_ = X 03_r_N= @ _|= = S:



### S -

_ - - - - - - Q t2F X == = = Ul FQ

= S--X= =El '' @ - =N = =S= n1 : -'

E zo@@@J
aR ° 4 8 12 16 20 24 28 32 36 o

Hours after Intake Figure 10. Model predictions

{curves) and observations (symbols) of the rateof urinary

excretion of radiolead

at early timesafter

administration

to adult human subjects. Sourcesof data are indicated


### bile or other secretions i the same

as that for ingested

lead. Lead is assumed

to be transferred directly from diffusible plasma to sweat. Losses in hair, nails, anddesquamated skin arerepresented

as a transfer from softtissue compartment

ST1to exct vte

1 WLo. 

### There have been several studies of the

r * s r s 

### rate or urlnary and tecal excretlon of lead after administration

of radiolead

to human

t * r 

### su)ects. It appears trom theurlnaryexcretion curve for intravenously

injected lead that a few percent

of administered

lead

moves to the urinary bladder contents with little or no delay

in the kidneys

(Fig.10). Urinary excretion curves for inhaled

or ingested lead reflect brief delays in absorptionto blood,

superimposed

on theexcretion curve forinjected

lead (Fig.10). For comparison

of modelpredictions

with

I



### observed urinary excretion rates in humans, it is assumed

that the urinary

bladder is emptied completely with each void- >
. i # ' g B,,,, v, g r' B 9#0 §' '' 'R0' §":.-

. "'' - AgS. I"JEmON

............................................................ ,.g.g,, l20 10| g l0t <#-

r#.# ::,. ............................ # .A,Z,O,V; tQ t02

.6#9#N4 2a. r.vU ,r,,e2,

.........................................

tg o >bB;<- r-.>>^

......... rD @ v i fl .fl BgX

'. B R ^ B,,# ,. #Be # Bee S ':#s'#':EpWe, ^,r, #B Bv# R # ,.; :',

............................................................ a. ##B; i.' ,.i:i.i. .,. ::



## M 2 

# l i @ | 01 0 l E0F XUggas 5j« t 1 | i 4 | g | | g g g g g , 8Eg > o.. 9 S

*_ Sg_ '''S'S"''''

_ g0WStt''''' '5''','-

O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

DaysafterInjection

v,:,i,s,,s,,v.B

>, Ze..v...a a va 8 8 :3:a48,. :,. o:; - -:B:3'.f.a V,.B::.:8 v x ::- . --:-: ::-:'::::'-:: :-::::::: :::::::--:i: Z 5 BW ;8 2# 4RB8

2 jB. 8 B R &#fR.S BB * 2;.4 2; ^8gg#R .-ix- <; - #Bg<>, ,eB, ,R,,:,

.......................................................... ...

_ ggglllggg8>gg I nON ,'. >''4,8, ,rR :R'.1 | * * g Y.,.g .E.

ffi ffi 1gggElEENg- unne W AS.E < - 3

B ,B,ki@,B,,B,

8,8.,. iB^N^g

B9B.,B gXsS.8rK c.z.2;.8.39 864lBEg

,x4,,Bog3-

............................................... N < 4 :8; s,,,4,,,,4,,o,,, x:B; ' a-

e i:B .-i

X iSB Ms'4. e aB

g7aa sBggaB Ba: szvReS4 t4 V-8a 8>V-2434a gG fgfR eVBaga E ffi 2 X g | | g g g g ;xv .X. xMxe v i B ce g - -2 

# ||||@<<gg0$1 

# s as <a, z, .srrsil .$ea'V8'. @B;v.vg a:R.Bs:

.a>s T (:

ae «oSl@X!W0023200

0 1 2 3 4 5 6 7 8 9 10 11 12 13

DaysafterInhalation

Figure 11. Model predictions {curves) and observations of the rates of urinary and fecal excretion of radiolead at early times after administration to adult human subjects. Urinary excretion data pointfor day 1 after injection is subject-weighted

mean of central values determined in Chamberlain et al. {27 > (6 subjects, mean 3.7%}, Booker et al. {31) {2 subjects, mean 5%}, Campbell

et al. {33} {2 subjects, mean 7.6%}, Hursh et al. (41} {2 subjects, mean 4.2%},

and Hursh

and Mercer (44} (4 subjects, mean 4.6%). Urinary excretion data point for day 1 after inhalation is subject-weighted mean of central values determinedin {27} (12 subjects, mean 2.7%},

(31} 2 subjects, mean 4.1%}, Hursh et al. (42}(10 subjects, mean 2.9%}, and (44} (4 subjects, mean 2.2%}. Fecal exoretion data point for day 1 following inhalation is subjectweighted mean of central values determined in (27} (12 subjects, mean 0.7%}and {42} (median 1.7% determined from scattered data on 10 subjects}. All other data points are from (27) and are

means for 7 or fewer subjects.


### ing. For most purposes one can remove the urinary bladder compartment

fromthe model or assume that removal

from the urinary bladder contents to urine follows first-order kinetics; a removal half-time of 0.1 day seems reasonable,

based on ICRP data (54). Typically,

2-5% of systemic

lead is excreted in urine during the first24 hr after administration

(Fig. 11) (31,41, 42,44). There is little loss in feces during the first day, but the fecal-to-urinary

excretion ratio is about O.S during days 2-14 after injection (Fig. 11 ) (27,28,32).

The fecal-to-urinary

excretion ratio is slightly higher(roughly

0.7-0.8) in the first 2 weeks after inhalation dueto ciliary

clearance and swallowing of a small portion of the lead deposited in the lungs

(Fig. 11;

i



### also see appendix). Urinary plus fecal osses during thefirst 20 days account for about

Volume 101, Number7, December 1993 607

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All use subject to JSTOR Terms and ConditionsResearch Advances c Leggett

sumed to be removed

from the urinary

path to the bladder

contents witha half-time

of 5 days. The transfer

ate from diffilsibleplasma to the urinary

bladder contents is 0.015

x (2000/day)

= 30/day. Human data on fecal excretion and on the urinary-to-fecal

excretion ratio for lead

arereproduced

reasonably

well by assigning 0.6% of lead leaving diffusible plasma tO the contentsof the small intestine. This is in addition to the amountassumed

to enter the small intestine contents via biliarysecretion,which

accounts forabout three-fourths of total fecalexcretion

in this model. The transfer ratefrom diffusible

plasma

tO the contents of the small intestine

is 0.006 x (2000/day)=

12/day. The difficulties

in measuring

the loss of lead in sweat are well recognized.

Results of

some studies indicatethat loss of lead in sweat can approach

or even exceed

that in urine under some conditions ( 13S13y), whileother

data suggest thatsweat

is not a significant excretion pathway for lead (27,14Q). The rate of transfer

fromplasma to sweat used in the present

model is a compromise valueand is consistent

with findings of Rabinowitz

and co-workers

(S for human subjectsingesting a lead isotope tracer over a period of months.

It is assumed that0.35%

of lead leaving diffusible plasma is removed

from the body in sweat. Thatis, the transfer

ratefrom diffusible

plasma to sweat is 0.0035 x (2000/day)

= 7/day. The model predicts

that total lossesof lead in sweat in the adult

are about 10%

as great as losses in urine during chronic exposure. It is difficult

to determine typical losses of lead by other excretion pathways. Hair is

a well-known

site of concentration

of internally deposited lead, but there is alsocontamination of hair from external sources (82). As described

earlier in the discussion

of the other soft tissues,

it is assumed

that 40% of outflow from ST1 is in hair, nails, and desquamated

skin, which yields a transfer ratefrom ST1 to excreta

of 0.00277/day. Fractional transfer from ST1 to excreta

was based primarily on measurements

of excreta from humansubjects

who ingested

a lead isotope tracer overa period

of months(S, but data from lesscontrolled

studies of lead in hair or nails were also considered (141-144). Xlth regard tO minor excretion pathways,

the model is intended only to approximate

cumulative

loss over an extendedperiod.

A precise treatment of the time-dependent

loss of lead in hair, for example, from the time of acute intake wouldrequire

a considerably

more complex excretion model (16).

Modifications Neded to Address Nonlinear Kinetics of Lead 

### The concentration

of lead in blood is not linearly related te the concentration

in plasma

or other fluids and tissues of the body,at least

when the bloodleadconcentration substantially

exceeds 25 pg/dl.This nonlinear behavior of leadis not completely understood

but may result

in large part from a reduced

rate of flow from plasma into RBCs

as certain lead-binding

components of these cells become saturated (17,18,20,3y). It has been suggested, for example, that the cell membrane

mayhave

a limited capacity forlead (17,145).

At low levels of exposure,

leadin RBCs

is associated primarily

with hemoglobin

(146). The Hb A2 component

of hemoglobin,

which represents only about 2% of the total hemoglobin

in human RBCs, maycontain one-half

tO two-thirds

of the leadin RBCs at relatively

low blood lead concentrations (39,146). There

appears to be saturation

of lead binding

to Hb A2 at low to moderate lead concentrations

and an increase

in the portionof lead found in the main hemoglobincomponent,

Hb A, which may also be saturable

at moderate

lead concentrations (32. There is also evidence that an elevated blood lead concentration

induces the formation of low-molecular-weight lead-binding proteins within the RBCs (32. The degree

of synthesis

of this protective lead-binding

protein may depend

on the leveland duration

of exposure,

and

somepersons

mayhave diminished

capacity forsynthesizing

thisprotein

(3y). Another potentially important leadbinding component of RBCs that may provide rapidly diminishing

bindingsites at moderate

blood lead concentrations is the metalloenzyme 6- am i no levuli nate dehydratase

(AIAD).Apparently,

lead ions

can replace

enzyme-activating

zinc ions at

a smallnumber

of sites on ALAD, resulting in inactivation

of AIAD and elevation of 5-aminolevulinic

acid (ALA)

in blood and urine ( 147). Urinary ALA increases nonlinearly,

perhaps exponentially,

with increases in the blood lead concentration, at leastat concentrations

exceeding 3040 pg/dl and possibly

much lower (132,146). Recent findings of Wetmur

and co-workers (147) indicate

that the blood lead concentration

is higher as an average

in individuals with the AIAD 1-2 or 2-2 isozyme phenotypes

than in individuals

with the

morecommon

AIAD 1-1 isozyme

phenotype. In the present

modelit is assumed

that the observed

nonlinear

relations between lead in blood and plasma, urine,or other fluids and tissues

result from a decrease

in the transfer

ratefrom diffusible

plasma to RBCs as the concentration

of lead in RBCs increases. The available

data do not clearly reveal a threshold

concentration

of lead in RBCsor blood at which a reduced rate of 

### flow into RBCs

should be introduced,

or
evenif such a threshold

exists. It is asE lllllllll

as _l w E l|||||||



### CL LLL: || . S

_



### C W | | ||||||| 

## 1||||||| ___=_ _ = = D3

_ _

|_:_X_ ==T__3_==__ Q X= _____|_g_ qs

__ t ASSS

.e |_|__w_ ; O Xi_ 0 5 10 15 20 25 30 35 40 46 90

Hours a"er Intake

Figure12. Model predictions (curve) and observations (circles) of the early urinary clearance of intravenously injected radiolead expressed in terms of the amount in blood plasma. Data points

are for one adulthuman

subject (27).


### 30% of the administered

amount in humans (28), compared

withabout

50% in beagles and perhaps 40-50% in baboons (18,49,82. The present model predicts that about 27% of administered

lead would be lost in urine

and feces during the first 20 days after injection into the adult human. 2IOn an adult male subject acutely exposed to Pb 43 years earlier, daily urinaryexcretion was estimated

to represent

about 0.0035% of the current

body burden as determined

by in vivo 

### mfflcurements

(107). Thepresent

model predicts that dailyurinary excretion at 43 years after acute intake of lead would be 0.0049%

of the current body burden. Some authors have expressed urinary clearance of lead in terms of the amount of lead in blood plasma or serum (Fig. 12) (27,36), but it is more

common to relate this quantity

tO 

### lead in the tOti 

### bloodvolume. In humans

exposed only tO 

### environmental lead, urinary dearance oflead is typ

### ically 0.02 (range,

0.015-0.03)

bloodvolumes per day(9,18,57,128-131),



### which is the value produced by the present model for blood lead concentrations

less than about 25 pg/dl. As indicated in Figure 13anddiscussed later in more detail, the daily urinary clearance may substantially

exceed this value at high levels of BPb. The nonlinear

relationship between lead in urine and lead in blood appears to be similar

tO 

### that between plasma lead andBPb, insofar as comparisons are possible. Inthis model, thenonlinear relationship

between urinary lead and BPb is assumed

tO 

### result from theincrease in diffusible

plasma lead as a fraction ofBPb and not fromnonlinear

kinetics in the kidneys. Human data on urinary

clearance of lead are reproduced

reasonably

well by assigning 1.5% of lead leaving diffusible plasma to the urinary

bladder contents, in addition

tO 

### the amount entering the bladder contents after retention in the urinary path. Recall that the latter accounts for 2%of lead leaving diffusible plasma and is as608 Environmental Health Perspectives

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All use subject to JSTOR Terms and ConditionsResearch Ad vances p Kinetic model for lead in humans

sumed here thatsucha threshold

does exist because a linear model appears

to reproduce the data

as well as a nonlinear

model at commonly encountered levels of lead, and some softwarepackages for solving compartmental

models do not allow the

useof nonlinear

kinetics. Because of the uncertainty

regarding the magnitude

(andexistence)

of the nonlinear threshold andsaturation

levels in RBCs and the potential

variation in these quantities from one exposure scenario to another, these are induded as user-selected

parameter values of the model,although

baselinevalues are given. It is assumed

thatthe deposition fraction

in RBCs remains at 0.24 until the leadconcentration,

Y,in RBCs

exceeds

a nonlinear

threshold level, T, expressed

in pg/dl RBC. If Y> T, the depositionfraction, D, in RBCs

is given by the equation

D= 0.24 x [1.0 - (Y-T)l(S-T)]l 5,

where S is an assumed

saturationconcentration of lead

in RBCs. This is an empirically derived expression that can be used to approximate

observed relationsbetween lead in blood and that in urineor plasma (Figs. 13 and 14, respeciively).

When Y> T, the other deposition

fractions in the model

are increased in proportion

tO their baseline values tO accommodate

the decrease

in the deposition

fraction for RBCs.

That is, the deposition

fEactions forcompartments

other than RBCsare increased

by the factor(1- D)/(1-0.24) = 1.316(1-D). The total transferrate from diffusible plasma to all destinations is assumedto remain at 2000/day under allconditions. Chamberlain

(18) suggested

that nonlinearkinetics of lead is evident above a blood lead concentration

of about 25 /dl, but other researchers

have suggested

that virtually linear kinetics are obeyed up to levels of 35-40 pg/dl blood. As a baseline value, the nonlinear

threshold concentration Tis setat 60 /dl RBC,

which corresponds to a blood lead concentration of about25 /dl.Selection

of a saturation

concentration, S, is complicated

by its apparent

dependence on the level

andduration

of exposure and potential

variation fromone person

tO another. As a baseline

value, S is set at 350 /dl RBC, based

on consideration

of the level of BPb at which the ratios urinary lead: BPb andplasma

lead: BPb begin tO increase rapidly in persons exposed for a long period

tO high levels

of lead (Figs. 13 and 14). A much lower value for S, perhaps on the order of 140 /dl RBC,maybe better for consideration

of a high, acuteintake

by a person with a history

of low intakes

(Fig.



### Results of controlled

studies in which the blood lead level of human volunteers _ 15_ AY-- ,ryAA>wZ | | | | < iY=G;a ? | | | | X =nsj_1|1S | | | |

X rh uX= X 1 | 11 |

o 12i4;_ | l | O L e !

_ m _;=

_ wwi a | l

ae =<=i

__ p3-- 2 2 _ ;wg 1X111 l I - 111 _|1S yy | @ -s -SZ1S

_ - s cJ _r . - -

-- - --- !l

_ - -|

_ E zo e | i1z1; -____A_ - -

_ w

_ n L

. Eiffiiiiiiiiii I iiY 11112 SYg

* | | w E |

_ _ Ey

_ Y3

@ | I 1 - 1 st l_

*1 1 [ '-1[1 *

_ | | Q tE - l | | 3 _Wn -." s.E i
. - B

- *l 13' - t1- X ilUl b | ' 7i1 S ir F gll @S ,,.n I S- n O B fi fi

0 20 40 60 80

Blood Pb (,ug/dl)

Figur0 13. Model predictions (solid curves} and observations {dashed curves) of the urinaryclearance of lead expressed in terms of the amount in blood. Shaded area indicates typical values for subjects chronically

exposed to low levels of lead {18,57, 115,130>.

Curves 1 and 2 summarize data for two volunteers receiving a short, heavy, controlled exposure to lead { 132). Curve 3 summarizes data of Cooper

et al. { 133}

on about 300 employees of a lead smelter and refinery. Curve 4 summarizes data of Skerfving

et al. ( 134)

for a lead worker. Model predictions assume an exposuredependent saturation concentration in RBCs.For

an acute intake by a person with a historyof low intakes, the assumed RBC saturation level is 140 pg/dl RBC. For chronic intake of high levels of lead, the assumed RBC saturation level is 350 pg/dl RBC.

was increased

to 35-40 pg/dl or higher

over a period of weeks or months (14S151)

seem more nearly consistent with the chronic exposure model than the acute exposure model indicated

above.That is, values of S dose to 350 pg/dl RBC appear to produce better agreement between model predictions

and those results

than do values near 140 pg/dl RBC. However, the data from those studies are too scatteredand the uncertainties in the amount of lead absorbed

to blood in each caseare too large to draw strong condusions

in this regard.The results of Kehoe (149) are inconsistent

with the strictly

linear model described in previous

sections, while the results of Griffin et al. (150 and Cools et al. (151) can be explained about as well with the linear model as the nonlinear model with S near

350 1lg/dl RBC.

Modification of Parameter Values for Application to Children ICRP Publication

56, Part 2 (22) introducesa generic

approach for development of age-specific

parameter

valuesfor calciumlike elements [also see Leggett (91)]. On the basis

of datafrom a large

number of studies on the fate of radioisotopes of calcium and related

elements in laboratory animals and humans,

it is postulated

that differences

with age in the biokinetics of these elements arise mainly from three related events: 1) increased

fractionaltransfer from plasma tO bone in children in 

### association witbthe relatively

greater ate of addition

of calcium

tO 

### bone in children --Mx

n - l |

> - w u X5 ; ; ; S S E Z

| g g | | |

_ . | | s a 3 | | | |

_ |

_ |- ^ 2 " S a

_ _ i i -i-i _8X

X __X__s E 15-=

____ __w_ L * _____L_ _|__ 1_-_l

o - |
0 20 40 60 80 100

BloodPb {,ug/dl}
Figure 14. Model predictions and observations of the nonlinear relation between blood lead and plasma lead. The dashed curves representing observations are fits to data of Manton and Cook {37) or deSilva (.


### than adults; 2) decreased

fractional transfer from plasma to softtissues

andexcreta

in children dueto relatively

greatercompetition from immature bone; and 3) an elevated rate of transfer fromnonexchangeable bone to diffusible

plasma in children dueto an elevated

rate of bone turnover. Except where there is evidence

tO 

### thecontrary, removal half-times from softtissues, bone surfaces, and exchangeable

bonevolume are assumed to be independent

of age. For some calciumlike

elements, including lead, available data are consistent with the assumption

that the size of the exchangeablepool of bone is greater in children than in adults. Within the context

of the present model structure orthe slightlysimpler structure used in ICRP Publication

56 (22), this means

that an atomentering bone has a smaller probability of reaching nonexchangeable

one in children

than in adults. This generic

approach appears to be consistent with information

on the agespecific kinetics of radiolead

in laboratory animals (13,14,50,120,127,152-158).

### For example, Mallon andco-workers

(13,14) conduded from data on baboons

exposed acutely or chronically

to 2l0Pb that skeletal uptake of absorbed

lead was much greater in rapidly growing animals than in more mature animals.In a 2l0Pb-ingestion experiment

with 10-day-old,

1 50-day-old, and adult

Macaca irus 

### monkeys,

skeletal tissues of the two younger

groupscontained a substantially

arger portion of systemic 2l0Pb than did those of adultmonkeys at 4 days after oral dosing (5(J). 

### In a similar experiment

with rhesus

monkeys, infants (ages 5-7 months)

excreted a substantially smaller fraction of the absorbed amount han did adults during the first 23 days after administration

(156). 

### Another perspective on differences

with age in the biological

behavior of leadis provided by autopsy

data on humansubjects exposed to 

### environmental

lead. These data can be used to 

### derive reference organ

Volume 101, Number 7, December 1993 609

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All use subject to JSTOR Terms and ConditionsTable 3. The distribution of lead in humans chronically exposed to a low level of lead throughout life, as calculated frompostmortem data and as predictedby this modela b
Age, years Tissue 1-5 6-9 11-16 20-30 40-50

Bone Postmortem

data 0.454.80 0.50-0.80 0.55-0.85 0.75-0.90 0.85-0.95 Model prediction 0.66 0.69 0.79 0.88 0.90
Blood Postmortem

data 0.03-0.08 0.03-0.08 0.03-0.08 0.015-0.035 0.008-0.02 Model prediction 0.045 0.055 0.04 0.025 0.02
Liver Postmortem

data 0.05-0.10 0.05-0.10 0.04-0.10 0.03-0.07 0.015-0.035 Model prediction 0.08 0.065 0.065 0.04 0.03 Kidneys Postmortem

data 0.007-0.015 0.006-0.015 0.005-0.010 0.003-0.007 0.002-0.004 Model prediction 0.012 0.009 0.006 0.004 0.003
Brain Postmortem

data 0.009-0.025 0.007-0.015 0.004-0.009 0.002-0.004 0.0008-0.002 Model prediction 0.018 0.01 0.004 0.002 0.002
Other Postmortem

data 0.12-0.35 0.10-0.32 0.08-0.30 0.04-0.15 0.02-0.08 Model prediction 0.185 0.17 0.09 0.05 0.045

aValues are expressed as fractions of total body lead. bModel predictions

are for ages 3, 7, 13, 25, and 45 years, respectively. Research Advances 0 Leggett



### distributions

of lead for different

age groups, andthese reference distributions

can serve as constraints

on modelparameters.Several

different adult populations have been studied, but reference

distributions for children must be based to a large extent on data from a single studyinvolving a large

number of subjects

from an industrialized

region of England,

including 18 subjects

of age 1-10 years

and 6 subjects of age 1 1-1 6 years( I 14). Thus, because of the substantial

uncertainties

in the accuracy

and universality

of the reference distributions

for children, they should be treated

only as firstestimates

rather than definitive data. The derived

reference organdistributions are indicated in Table 3, where they

are represented

as ranges of values rather than point estimates

to emphasize

the uncertainties

involved. The method

of development

of these uncertainty

ranges will bedescribed

in detail in another paper. Briefly, baseline contents (expressed asfractions of the total-body

content) of lead in different tissues of a middle-aged

adult male are based on medians

of leadconcentrations determined

in the relatively

detailed investigations

byGross andco-workers (11X, 

### Barry

(113,114, 

### and

Tipton and co-workers

(15S161). 

### To reduce

results from these three different sudies to a common basis,

reported concentrations

from each study were normalized to a liverconcentration

of 1 ppmwet weight.Concentrations

reported by Barry (114) were used as baseline values for the younger ages. Datafrom

these studies were compared with findings from a variety oflesscomprehensive post-mortem

studies in an effort O 

### determine howwell these

baseline organ contents might represent anarbitrary

study group. The ranges

of values indicated in Table 3 were derived from a kind of parameter uncertainty

analysis in which the major parameters ued to derive the reference distributions

were variedsimultaneously within reasonable ranges of uncertainty. It was considered,

for example, that 1) the relative concentrations

oflead in different organs vary from one study group to another; 2) there may beproblems

associated with analytical techniques andcontamination of samples,

particularly

for tissues with low concentrations

of lead; 3) the sampling sites may notbe representative

of the whole organ or tissue; and 4) themass of tissue represented

by a reported

concentration is often not well known (e.g.,trabecular bone usually contains more softtissue than bone tissue). The derived ranges of values (Table 3) cannot be interpreted

as precise probability statements, but it is likely that the true relative

organ contents under conditions

of chronic

exposure would fall within the indicated ranges. In the development of the present model forchildren,

the reference

distributions were first used to test provisionalparameter values for children that were based on
a set ofgeneric assumptions

concerningdifferences with age in the behavior

of calciumlike elements. Some adjustments

of the provisional

parameter values were then madeto obtain acceptable agreement between model predictions

and the reference distributions

for young children. Itwas found that the predicted age-specificdistributions varied little withthe exposure

scenario, provided the rate of uptake oflead to blood was not radically altered over a period of a fewmonths.

Thus, predictions

were based on a simple

scenario of constant uptake (20 pg/day)

to blood throughout life. In this model, thelead content of the various compartments

at birth are derived from the assumed

content in themother's blood. The concentration

f lead in blood at birth is assumed to be 0.85times

that of the mother's

blood, based on a variety

of studies (167). The relative contents ofbone, blood, liver, kidneys, brain, and other soft tissues atbirth are assumed to be0.32, 0.07, 0.055,0.01, 0.045,and

0.5, respectively, based mainly on data of Barry

(114); 

### for multiple-compartment

organs, thecontents atbirth are assumed to reside in thelongestterm compartment.

For the exposure

scenario considered here, theconcentration

f lead in the mother's blood is assumed

tO 

### be that calculated for a 25-year-old

person with chronic uptake of 20 pg Pb/day. The provisional

ge-specific

parameter values were based on thefollowing

eneric assumptions

(1-5 below),which were applied earlier

tO 

### the alkaline

earthelements (22,91). Generic assumption

1. 

### Fractional

deposition on bone surfaces is proportional

to the rateof addition

of calcium

due to modeling and remodeling

of the given bone type (trabecular orcortical).

Theestimated average calcium addition rate for adults (0.25 g/day)and the deposition fraction for bone in thetypical

adult serve
as the points

of reference.

The model

for the rate ofaddition ofcalcium to theskeleton is described

elsewhere (91). Generic assumption

2. 

### The total transfer rate from nonexchangeable

bone volume is equal to the bone

turnover rate and thus varies with age. Themodel

for the rate of turnover of cortical and trabecular bone in children is described

elsewhere (21,97). Generic assumption

3. 

### At allages,

cortical bone represents

80% and trabecular bone the remaining

20%of total bone (97). This assumption

is based on measurements on the adult

human skeleton (54). The relative

amounts of cortical and trabecular bone in children cannot be estimated with much confidence,

particularly for the first

fewyears of life.As it turns out, model predictions are fairly insensitive to the division between cortical andtrabecular bone in children because, asindicated by data for the alkaline earth elements and depicted in thismodel,

there is littledistinction between trabecular andcortical bone in children with regard to the kinetics ofcalciumlike

elements. The model depicts trabecular nd cortical bone as growing at the same rate and as having fairly similar remodeling

rates during childhood. Bone remodeling

rates are assumed to be identical in the two bone

types during infancy and to diverge gradually during childhood and adolescence.

As a consequence

of

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### generic assumption

1, the estimated

trabecular to cortical deposition ratio ofa calciumlike element increases from 0.25 in infants (since there is assumed to be onefourth as much trabecular s cortical bone and the growth

and turnover

rates are assumed

tO 

### be the same

forthe twobone types in infants) to 0.34 atage 10years, for example, and to 1.25 in mature

adults. Boneoriginally

laid downas trabecular bone butconverted

to compact

boneduring growth

is assumed

tO 

### have beencortical bone throughout

its existence. Generic assumption



### 4. In children, deposition

fractions for soft tissues

and excreta are reduced uniformly because of the higher

deposition

in bone.This assumption is intended to apply to thedistribution that would be seen after the early, rapid exchange between diffusible plasma and extravascular

fluids is largely complete. Thus, it iS 

### implemented

by ignoring

any potential short-term effects on the extravascular fluid compartment,

EVF.Compartment EVF is assumed to receive 50% of instantaneous

outflow from diffusible plasma at all ages,

and reduced

transfer from diffusible plasma to softtissues

and excreta of children is described

in terms of the remaining

50% of outflow fromdiffusible plasma. As an example,

thedeposition fraction

assigned to all bone

surfaces combined is 0.08for mature adults and, as derived from generic assumption

1, 0.24 forinfants.

For the infant, the deposition fractions for soft tissue

compartments

or excretion pathways are determined

as (0.5- 0.24)/(0.5-0.08)

= 0.619 times

the corresponding deposition fractions for adults. This approach

is reasonably

consistent withthe limited

age-specific

data on lead in nonhuman

primates (13,50,156). Generic assumption

5. 

### Removal

halftimes from soft tissues, bone surfaces, and exchangeable

bone volume areindependentof age.

As described

later, it seems appropriate

to relax this assumption

for the

case of lead in theliver

and kidneys. Also, limited information

suggests that the rate of removal of alkaline earth elements from exchangeable

bone may be greater in children thanin adults,

but the present

assumption seems reasonable untilage-specific rates can be better

supported and quantified.

Note that this assumption applies to total outflow from bone surfaces andexchangeable

bone volume anddoes not address the destination ofoutflow. A sixth assumption

regarding the relative exchangeability

of bonedeposits

in children and adults

is applied in ICRP Publication

56 (22^) on an element-by-element basis.

Thereis evidence

that exchangeability

of strontium

decreases with increasing bone age, but it probably should not be assumed

that this phenomenon applies uniformly to all alkaline

earthelements because it appears to be lesspronounced for calcium

than for strontium (91). An assumption

of elevatedexchangeability ofbone deposits in children leads to improved agreement between modelpredictions and autopsy

data on persons exposed to environmental

90Sr and thus is applied by ICRP (22) to strontium.

This assumption

could notbe tested

for barium and radium and is not applied in the ICRP document to these elements. Theassumption is implemented

for strontium

by assigning reater fractional transfer from bone surfaces to diffusible

plasma in children thanin adults.

It couldbe implemented in other ways,- such asbyassigning

a greater fractional return fromexchangeable bone volume to bone surfaces in children, but the available

data on strontium

seem consistent with the requirement

that the elevated exchange ofbone strontium in children bemanifested

fairly rapidly. There is no direct

evidence of decreasingexchangeability

of lead with increasing bone age. The situation

forlead is otherwise similar to that for strontium, however, in that an assumption

of elevated

exchangeability

of bone deposits in children helps reduce discrepancies

betweenpredictions of a provisional

model based

on assumptions

1-5 and autopsy

datafor environmentally

exposed children.Therefore, thefollowing

assumption

is made for lead.

Assumption 

### 6. There

is greaterfractional transfer from bone surfaces to diffusible plasma in children than in adults. Byanalogy with strontium, it is assumed

thatfractional return from bone surfaces to plasma is 1.25 times

higher at ages 0-15 years than in adults. For lead, thismeans

that 1.25 x 50% = 62.5%, rounded to 65%, of the amount

leaving bone surfaces goes to diffusible plasma and 35%goes to exchangeable bone volume. As the total transfer rate from bonesurfaces is assumed to be 1/day,

as in adults (see generic

assumption

5), the transfer rate from (trabecular o cortical) bonesurfaces to diffusible

plasma in children

is 0.65 x (1/day) = 0.65/day,

and the transfer rate from bonesurfaces

to exchangeable bone volume is 0.35/day. The addition ofassumption

6 improves agreement between model predictions

and reference distributions

for children,particularly for bone, but noticeable

discrepanr 

### cles remaln

tor some compartments

at

some ages. For example, the liver andkidneys do not appear to beimportant

repositories of lead in young children, butif the parameter values foradults are applied

tO 

### these organs during childhood, the model predicts substantial buildup in the first few years of life, duemainly tO 

### accumulation in the

long-term compartments

assumed to exist in each organ. Thus, it seemsreasonable to reduce the removal

half-time for these compartments

inyoung children. Assumption

7. 

### The removal

half-time from thelong-term

compartments

of liver and kidneys

to diffusible

plasma is 100 days for ages 0-5 years. Theremoval

halftime forages 10 years and 15 years

is the

same as for adults

(1 year). Recall that transfer rates for ages intermediate

to those indicated in Table 1 are calculated by linear interpolation

(with age) of thetransfer rates given in the table. Although some discrepancies

remain between model predictions

andreference distributions

after application of theseven assumptions

indicated above, furthercomplications of themodel

based on thesereference distributions

for children

do not appear to be justified for purposes of radiation protection. For example, assumptions 1-7 yield higher

fractional contentin blood and lower fractional content in other soft tissues than indicated by thereference distributions

for children.

Estimates of dosefrom internally depositedradioisotopes of lead are notaltered much,however, byforcing the model to fitthe reference values for other soft tissues and blood; this is because thepredicted

and referencedistributions

agreereasonably

well with regard to the sum ofthe fractional contents of other soft tissues and blood, and, in calculation of radiation

doses, radiological decays in blood are assigned primarily to the organs and tissues making upother soft

tissues. 

### While the ability to predict the level of lead in blood in chronically

exposedchildren may not be critical

for radiationprotection purposes, the BPb level is the primary index used in the development

of exposure guidance for stable lead. Thus, for consideration

of lead as a chemical toxin,it seems

worthwhile

to introduce greater detail intothemodel

to reproduce

more closely the fractional

contents in blood indicated by the reference

distributions for children. Data on nonhuman

primates (13,50) 

### suggest that there may besmaller uptake of lead by RBCs and/or faster removal from RBCs in young animals thanin mature animals. Also, model predictions

forchildren can be brought

intolinebetter

with reference fractional contents of blood in children and data on intakes

and blood levels of lead in infants (163) by assigning to the younger age groups either a smaller deposition fraction to RBCs or a shorter removal half-time to RBCs. There is little basis for choosingbetween these two 

### approaches,

except hat within thepresent scheme it is simpler

to assign a shorter removal half-time.

Volume 101, Number 7, December 1993 611

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### Summary and Conclusions
Several different ypes of information

contribute to ourunderstanding

of the behavior of lead in the human

body.Theseinclude results of lead tracer studies on healthy

adult human volunteers;

measurements

of lead in autopsy samples from environmentally exposed humans of all ages;

results of lead balance studies on adulthumans;

bioassay data and autopsy

measurements

on persons occupationally

exposed

tO lead; datafrom controlled

studies of the behavior

of radiolead in laboratory

animals at different stages of life; and dataon the age-specific kinetics of the chemically and, in many respects, physiologically

similar alkaline earthelements

in humans

and laboratory animals. In thispaper

an attempt

hasbeen made to synthesize

all of the different

sources of information

into an age-specific

biokinetic model for lead. The data were organized within a compartmental

model structure originally developed forconsideration

of the age-specific

biokinetics

of a class of calciumlikeradionudides.

The model

structurerepresents a compromise

betweenbiological realism and practical

considerations

regarding the quantity

and quality

of information available to determine

parameter

values. Transport of lead between compartments

i assumed

tO follow linear, first-order kinetics provided the concentration

in red blood cells remains

below a nonlinear

threshold level, but a nonlinear

elation betweenplasma lead and redblood

cell leadis modeled for concentrations

above that level. The modelappears

to be a fairly

accurate predictor for adult humans exposed to relatively low levels of lead. It is proposed onlyas a reasonable

starting point for modeling the biokinetics

of lead in children

or the kinetics

of lead at high levels

of exposure. The modular

design of this modelis intended to allow researchers

to modifyspecific parameter values or model components to address pecial problems in leadtoxicology or to incorporate

new information.

For example, one could substitute

a detailed model of the brain

for the present

singlecompartment

brain without adjusting other components

of themodel. 

### Appendix
Respio and

4iZ Tract Models l;or

T esd Rzspiratoty

TractModel Fractional deposition

of inhaled leadin the lungs varies

with the size of the inhaled material, the breathing

rate, and otherfactors. A value of about 0.354.40 maybe a reasonable

central estimate, but deposition

firactions as low as 0.15 or as 

### high as 0.75

may not 

### be uncommon 

### (18,27,31,42,44, 45,128,150,164. Assumption 

### 8. The removal half-time from RBCs isshorter inyoung children than in adults. The following removal half-times from RBCs to diffusible

plasma re chosen for reasonable consistency with the reference distributions:

ages 0-1 years, 1.5 days; ages 5 years, 2.5days; ages 2 10 years, 5 days. The derived reference distributions

indicate that the fractional content of other soft tissues is considerably

greater in youngchildren than in adults. The relatively highcontentestimated

for thisgroup

of tissues at young ages can be traced to thehigh

portion of the body weight represented byskin and fat and the highreported

concentrations of lead in fat in young childrencompared with adults. Thehigh reportedconcentration oflead in fat in children could be partly an artifact of theautopsy

data, given the considerable

technical problems in obtaining representative

samples of fatand accurately determining

thelow concentrations of lead in those samples on a freshweight basis. In this model, the indicated higher content of other soft tissues is taken at face value and is explained

by a higher deposition fraction forcompartment

ST1 because of its association

with skin and fat. The elevated uptake by ST1 is balanced by reducing inflow to the rapid-turnover

softtissue compartment,

STO, one of whose purposes in this model is tO 

### receive

leftover leadafter the other compartments

have been addressed. Assumption

9. 

### The deposition

fraction in the intermediate-turnover

compartment, ST1, is two times higher atages 0-15 years than in adults. The higher

deposition in ST1 at theseagesis balanced by lower deposition in STO. The brain is not considered

as a separate organ in ICRP's model for lead (2X but is part of other softtissues.

Although autopsy results indicate that theconcentration of lead in brain may be lower in children than in adults, thebrain is estimated

tO 

### contain a much higher portion of total body lead in infants and young children than adults because of its relatively

greater

mass (as a percentage

oftotal body mass) at the younger

ages. This is supported

by comparative

data on mature and immature baboons administered

radiolead (18). In this model, therelatively

higher content of brain at young ages is explained

by a higher deposition fraction for brain. Assumption

10. 

### The deposition fraction in brain is three times higher at ages 0-1 years than in adults, due to the relatively greater mass of brain as a percentage

of total body weight. Thedeposition

fraction for brain is assumed to dedine linearly with age to 5 years,

when the adult

value is reached. Thehigher

deposition in brain at ages 0-5 years is balanced

by assigning

a slightly lower deposition fraction to STO. Experimental data for human

subjects indicate that 85% or more of deposited lead is deared from the lungs with an effective biologicalhalf-timeon the orderof 0.2-0.6 day, if clearance is expressed

in termsof one or tWO components (27,31, 32,42,44,45,165,166).

Similarly, a biological half-time of about 0.5 day has been found for dogs (167). A more detailed description

was givenby Chamberlain and co-workers

(27), who found that for deg0o3sited 203PbO, 2°3Pb(NO3)2,

or "dean" Pb-labeled

exhaustaerosols,approximately22% was cleared

with Tll2 = 0.8 hr, 34% with T1/2 = 2.5 hr, 33%

with T1/2

= 9 hr, and

2102% with Tll2 = 44 hr. For

carbonaceous 3Pb-labeled

exhaust aerosols, approximately

29% was deared with T1/2 = 0.5 hr, 50% with T1/2

= 4.5 hr, 6% with T1/2 = 24 hr, and 15%

with T1/2 = 220 hr. Fractional

uptake of deposited

lead tO blood dependson the form and particle size of inhaled lead. For submicrometer aerosols there appears

to be little ciliary dearance of deposited

lead. For example, results of Hursh et al. (47) andWellset al. (3X indicate

that about95% of deposited lead was absorbed

directly

tO blood. When inhaled as a vapor,

as muchas 3540% of deposited

lead might be removed

to the stomach, and the rest is absorbed

directly to blood(31). Basedon the above information, the following lung model was adopted for comparison of model predictions with observations

on the behavior

of inhaled lead. The deposition

fraction for unknown forms of lead is set at 0.37. (A lungdeposition fraction

was not needed for present purposes, because data from inhalation studies were related to the deposited amount rather than the inhaled

amount.) Of the deposited

amount, 20% is assumed to be dared with Tl/2 = 1 hr, 35% with Tl/2 = 3 hr, 35% with Tl/2 = 9 hr, and 10% with Tl/2 = 2 days, with 95% of deared lead absorbed directly to bloodand 5% moving to the stomach via ciliary dearance. Greater ciliary clearance may be expected in industrialexposures, where aerosol particles are often larger

(18), or with lead inhaled as a vapor (31). It is assumed that the behavior

of leaddeposited in the lungs

is independent

of age.
Gasjrogn EractModel For persons

2 18 years

old, movement

of lead throughthe gastrointestinal tract is assumed to follow the gastrointestinal

tract modelof the ICRP (12). That is, material is assumed

to move in sequence

through four segments of the GI tract:

stomach (S), 

### small intestine (SI), upper large intestine (ULI), and lower large intestine (LLI). Absorption

from the gastrointestinal

tract is assumed

to occur onlyin segment

SI.

612 Environmental Health Perspectives

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC

All use subject to JSTOR Terms and ConditionsResearch Advances @ Kinetic model for lead in humans

13. Mallon

RP. A metabolic

model of lead kinetics based uponmeasuled

organ burdens during chronic exposure experiments

withinfant

and juvenile baboons (dissertation).

New York New York University,

1983. 14. Kneip TJ,Mallon

RP, Harley NH. Biokinetic modelling for mammalian

leadmetabolism. Neurotoxicology

4: 189- 192(1983)

. 15. Marcus

AH. Multicompartment

kinetic models for lead. I. Bone diffusion models for long-term retention. Environ Res 36:441458 (1985). 16. Marcus

AH.Multicompartment

kinetic models for lead. II. Linear kinetics and variableabsorption in humans

without excessive leadexposures. Environ Res 36:459-472(1985). 17. Marcus

AH. Multicompartment

kinetic models for lead. III. Lead in blood plasma nderythrocytes. Environ Res 36:473-489(1985). 18. Chamberlain

AC. Prediction

of response

of blood lead to airborne

anddietary

lead from volunteer experiments

with lead isotopes. Proc R Soc London B 224: 149-182(1985). 19. Bert JL, van Dusen LJ, Grace JR A generalized model for theprediction

of lead body burdens. Environ Res 48:117-127(1989). 20. O'Flaherty

EJ. Physiologically

based models for bone-seeking

elements. II. Kinetics

of leaddisposition in rats. Toxicol Appl Pharmacol 111:313-331(1991). 21. International

Commission

on Radiological Protection. Age-dependent

doses to members

of the public from intake of radionudides.

ICRP Publication

56, Part 1. Oxford:

Pergamon Press, 1989. 22. International

Commission

on Radiological Protection. Age-dependent

doses to members

of the public from intake of radionudides.

ICRP Publication

56, Part 2. Oxford:Pergarnon

Press (1993)- 23. ggett RW.

A retention-excretion

model for americium

in humans.

Health Phys 62:288- 310(1992). 24. Leggett

RW. A model of theretention,

translocation, andexcretion

of systemic

plutonium. Health Phys 49:1115-1137(1985). 25. Leggett

RW, Eckerman KF, Wllliams LR An elementary method forimplementing

complex biokinetic models. Health Phys 64:260- 278(1993). 26. Vander

AJ, Taylor DL, Kalitis

K, Mouw DR, Victery W. Renal handling of leadin dogs: clearance studies. Am J Physiol

233:F532- F538(1977). 27. Chambedain

AC,Heard

MJ, Little P, Newton D, Wells AC, Wlffen

RD. Investigations

into lead from motor vehicles. AERE-R 9198. Oxon, UK Harwell,

1978. 28. Heard

MJ, Chamberlain

AC. Uptake oflead by human skeleton andcomparative

metabolism oflead and alkaline earth elements. Health Phys 47:857-865(1984). 29. Pfordte K. Ober die Blei-SerumproteinBindung. Acta Biol Med Germ

27:527-532 (1971). 30. Griffin

RM,Matson

WR The assessment

of individual variability

O trace metal insult:lowmolecular-weight

metal complexing

agents as indicators of trace metal insult. Am Ind Hyg Assoc 33:373-377(1972). 31. Booker

DV, Chamberlain

AC, NewtonD,

Stott ANB.

Uptake of radioactive

leadfollowing inhalation

and injection. Br J Radiol 42:457-466(1969). 32. Wells AC, Venn JB, Heard MJ. Deposition

in the lung and uptake to blood of motor exhaust labelled with Pb-203. In: Inhaledparticles IV, Proceedings

of a symposium

of the 

### Transfer from one segment

o another

is assumed to follow first-order kinetics. In adults, transfer rates outof segments

S, SI, ULI, and LLI are 24, 6, 1.85,

and 1/day, respectively.

For children age0-12 years, the removal half-time from each segment is assumed to be 0.6 times

the adult value, based on data of Corazziari

and co-workers (168). Values

for ages 12-18 years

are based on interpolation

of the 12-year

and 18-year values. Lead transferred from the liver or from plasma into the contents

of thegastrointestinal

tract is assigned to segment SI and is assumed

to be reabsorbed to plasma tthe same rate as ingested lead. Absorption

of lead from the gastrointestinal tract has been studied extensively anddepends

trongly on a variety

of factors, induding the level of calcium,

phosphorus, zinc, iron, fat, protein,

andvitamin D present in the intestines; the body's iron or zinc status;

the amount

of lead administered;

the physical

and chemical form administered;

and thetime of fasting (6,13,169-17i. 

### It is not surprising, then, that a large range of gastrointestinal absorption fractions (0.01-0.8) have been reported. Most measurements

on adult humans have fallen in the range

0.03-0.2 for intake with solids (9,27,173,176-180, 

### 0.08-0.30forintake

withliquid

between meals (27,181), 

### and

0.3-0.7 foringestion withliquids

after several hours of fasting (9,27,1 73,1 77,1 79,1 80)

. 

### Most balance studies have indicated values of 10% or less (101,149,182-184, 

### but reanalysis of balance data in view of current information

on endogenous

fecal excretion of leadindicates thatan estimate

of 0.15 or greater might bemore appropriate

(27,128). 

### Balance studies uggest that infants and children may absorb

40% or more of ingested lead (185-188), but results of these studies are highly variable andinconclusive. Dataon monkeys

(50X156 

### and rats (152,157,189,190 

### generally indicate substantially

higher absorption

of lead in growing than in mature animals. In ICRP Publication

56 (22, 

### absorption fractions

assigned to infants,

ages 1-15 years,

and adults

are 0.6, 0.4, and 0.2, respectively.

In this paper

the same pattern is assumed,

but the values

are reduced by 25%, to 0.45 in infants

(defined here as 0-100 days

of age),0.3 at ages 1-15 years,

and 0.15 in adults

(2 25 years). Linearly interpolated

values are used for ages between 100 days and 1 year

or between 15 years and 25 years. Forexample, the value

for age 20 years

is (0.5 x 0.3)+(0.5 x 0.15) = 0.225.

REFERENCES

1. Drasch GA, Bohm J, Baur C. Lead in human bones. Investigations

on anoccupationally

nonexposed population in Southern

Bavaria (FRG). I. Adults. Sci Total Environ 64:303-315 (1987). 2. Drasch

GA, Ott J. Lead

in human

bones. Investigations

on an occupationally

nonexposed population in Southern

Bavaria (FRG). II. Children.

Sci Total Environ

68:61-69 (1988). 3. Ducoffre

G, Claeys F,Bruaux P.Lowering

time trend of bloodleadlevels

in Belgium

since 1978. Environ Res 51:25-34(1990). 4. Lippmann

M. Alice Hamilton Lectule. Lead and human

health: background

and recent findings. Envilon Res 51:1-24(1990). 5. Davis JM, Svendsgaard

DJ. Lead and child development.

Nature 329:297-300(1987). 6. Miller GD, Massaro

TF, Massaro

EJ.Interactions between lead and essential elements, a review. Neurotoxicology

11:99-120(1990). 7. Mushak

P. Defining

lead as the premiereenvilonmental health issue for children in America criteria and their quantitative

application. Environ Res 59:281-309(1992). 8. Abdelnour

J, Wheeler GL, Forbes RM. A compartment model of lead uptake in mature and young adult male rats. In: Trace substances in environmental

health, VIII (Hemphill

DD, ed). Columbia,

MO: University

of Missouri Press, 1974;411-416. 9. Rabinowitz

MB,Wetherill

GW, Kopple

JD. Kinetic analysis of lead metabolism

in healthy humans. J Clin Invest 58:266270(1976). 10. Bernard

SR. Dosimetric

data and metabolic model for lead. Health Phys 32:44 46(1977). 11. Batschela

E, Brand L, Steiner A. On thekinetics of lead in the human

body. J Math Biol 8:15-23(1979). 12. International

Commission

on Radiological Protection. Limits for intakes by workers. ICRP Publication

30. Oxford:

Pergamon Press, 1979.

Volume 101, Number7, December 1993 613

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC

All use subject to JSTOR Terms and ConditionsResearch Advances @ Leggett

British Occupational Hygiene Society, (Walton WH, McGovern

B, eds). Oxford: Pergamon Press, 1975; 175-189. 33. Campbell

BC, Meredith

PA, MooreMR, Watson WS. Kinetics

of lead followingintravenous administration

i man. Toxicol Lett 21:231-235(1984). 34. Hart HE, Spencer

H. Vascular

andextravascular calcium interchange

in man determined withradioactive

calcium. Radiat Res 67:149- 161(1976). 35. Brunekreef

B. The relationship

between air lead and blood lead in children, a critical review. Sci Total Environ 38:79-123(1984). 36. Manton

WI,Malloy

CR. Distribution

of lead in body fluids after ingestion of soft solder. Br J Ind Med 40:51-57(1983). 37. Manton

WI, Cook JD. High accuracy (stable isotopedilution)measurements of lead in

serum and cerebrospinal

fluid. Br J IndMed 41:313-319(1984). 38. Barton

JC. Retention

of radiolead

by human erythrocytes

in vitro. Toxicol Appl Pharmacol 99:314-322(1989). 39. Raghaven

SRV, Culver

BD, Gonick HC. Erythrocyte

lad-binding

protein afteroccupational exposure. Environ Res22:264-270 (1980). 40. Stover

BJ. 2l2Pb (ThB) tracer studies in adult beagle dogs. Proc Soc Exp Biol Med 100: 269-272(1959). 41. Hursh

JB, Suomela

J. Absorption

of Pb-212 from the gastrointestinal

tract of man. Acta Radiol Ther Phys Biol 7:108-120(1968). 42. Hursh

JB, Schraub

A, Sattler EL,Hofmann HP. Fate of Pb-212 inhaled by humansubjects. Health Phys 16:257-267(1969). 43. Hevesy

G, Nylin G. Application

of thorium B labelled

red corpuscles

in blood volume studies. Circ Res1:102-111(1953). 44. Hursh

JB, Mercer

TT. Measurement

of Pb212 loss rate from human lungs. J Appl Physiol 28:268-274(1970). 45. Morrow

PE, Beiter

H, Amato

F, GibbFR. Pulmonary

retention of lead, an experimental study in man. Environ Res 21:373-384 (1980). 46. Rabinowitz

MB, Wetherill

GW, Kopple

JD. Lead metabolism

in the normalhuman: Stable isotope studies. Science 182:725-727 (1973)- 47. Rabinowitz

MB, Wetherill

GW, Kopple

JD. Studies of human lead metabolism

by use of stable isotope tracers. Environ HealthPerspect 7:145-153(1974). 48. Araki

S, Aono H, Yokoyama

K, Murata

K. Filterable plasma concentration,

glomerular filtration, tubular balance, and renal clearance of heavy metals and organic

substances

in metal workers. Arch Environ Health 41:21; 221(1986). 49. Lloyd RD, Mays CW, Atherton DR, Bruenger FW. Pb-210 studiesin beagles. Health Phys 28:575-583(1975). 50. Willes

RF, Lok E, Truelove

JF,Sundaram

A. Retention and tissue distribution of Pb210(NO3)2

administered

orally to infant and adult monkeys.

J Toxicol Environ

Health 3:395-406(1977). 51. Domanski

T, Trojanowska

B. Studies

on metabolic kinetics of lead andalkaline

arth elements (Ca, Ba). Acta Physiol Pol 31: 439 447(1980). 52. Gregus

Z, Klaassen

CD. Disposition

of metals in rats,

a comparative

study of fecal,urinary, and biliary excretion and tissuedistributionof eighteen

metals. Toxicol ApplPharmacol 85:2g38(1986). 53. deSilva PE.Determination

of lead in plasma and studies on its relationship

to lead in erythrocytes. BrJ Ind Med 38:209-217(1981). 54. International

Commission

on Radiological Protection.

Report of thetask group on reference man. ICRPPublication 23. Oxford: Pergamon Press, 1975. 55. Cavalleri

A, Minoia C, Pozzoli L, Baruffini

A. Determination

ofplasma lead levels in normal subjects and in lead-exposed

workers. Br J Ind Med 35:21-26(1978). 56. Everson

J, Patterson

CC. "Ultra-clean"

isotopedilution/mass

pectrometric

analyses for lead in human

blood plasma

indicate that most reported values are artificially high. Clin Chem 26:1603-1607(1980). 57. Minoia

C, Sabbioni

E, Apostoli

P, Pietra R, Pozzoli L, Gallorini

M, Nicolaou

G, Alessio L, Capodaglio

E. Trace element referencevalues in tissues

from inhabitants

of the European community.

I A study of46 elements

in urine, blood, and serum

of Italian subjects. Sci Total Environ 95:89-105(1990). 58. Orten

JM, Neuhaus

OW. Human

biochemistry. St.Louis, MO: C. V. Mosby

Co., 1982. 59. Harrison

GE, Carr TEF, Sutton A. Distribution of radioactive

calcium, strontium, barium and radium

following intravenous injection into a healthy man. Int J Radiat Biol 13:235-247(1967)

. 60. Aub JC, Robb GP, Rossmeisl

E. Significance of bone trabeculae

in the treatment

of lead poisoning.

Lead studies XVII. Am J Public Health 22:825-830(1932). 61. Sobel AE, Yuska

H, Peters DD, Kramer

B. The biochemical

behavior of lead. I. Influence of calcium,

phosphorus,

and vitamin

D on lead in blood and bone. J Biochem 132: 239-265(1940). 62. McLean

R, Calhoun

JA, Aub JC. Migration of inorganic

salts in bone as measured by radioactive lead and byalizarin. Arch Ind Hyg Occup Med 9:113-121(1954). 63. Pounds

JG, Morrison D, Wright R, Casciano DA, Shaddock

JG.Effect of lead on calciummediated cell functionin the isolated rat hepatocyte.

Toxicol Appl Pharmacol

63: 402-408(1982). 64. Simons

TJB. Lead-calcium

interactions

and lead toxicity. In: Handbook

of Experimental Pharmacology,

vol 83. Berlin:Springer-Verlag, 1988;509-525. 65. Norrdin

RW, Arnold JS.Comparison

of47Ca accumulation

in samples

of trabecular

and cortical bone and its retention

in ribs,humerus, and femur. In:Bonehistomorphometry(Iee WSS, Parfitt AM,eds). Paris: Societe Nouvelle de Publications

Medicales et Dentaires, 1980;499-500. 66. El-Sharkawi

AM, Morgan

WD, Cobbold

S, Jaib MBM, Evans CJ, Somervaille

LJ, Chettle DR, Scott MC. Unexpected

mobilisation

of leadduring

cisplatin chemotherapy.

Lancet 2:249-250(1986). 67. Batuman V, Wedeen RP, Bogden JD, Balestra DJ, Jones K, Schidlovsky

G. Reducing bone lead content by chelation

treatment

. . , *

. . . ln c lronlc eaa polsonlng:

an ln vlvo x-ray fluorescence

andbone biopsy study. Environ Res 48:70-75(1989). 68. Petrow

HG. The metabolic

and dosimetric significance

of 210Pb and226Ra ratios in the bone of radium dial painters. In:Proceedings of the first international

congress of radiation protection (Snyder

WS, ed). New York: Pergamon Press, 1966;727-741. 69. Blanchard

RL.Radiobiology-correlation f lead-210 with strontium-90

in human bones. Nature

211:995-996(1966). 70. StrehlowCD, Kneip TJ. The distribution of lead and zinc in the human skeleton. Am Ind Hyg Assoc

J 30:372-378(1969). 71. Hursh JB. Retention of Pb-210 in beagle dogs. HealthPhys25:29-35(1973). 72. Van de Vyver FL, D'Haese PC, Visser WX, Elseviers MM, Knippenberg LJ, Lamberts LV, Wedeen RP, De Broe ME. Bone lead in dialysis patients. Kidney Int 33:601-607 (1988). 73. VincentJ. Les remaniements de l'os compact
marque a l'adie de plomb. Rev Belge Path Med Exper

26: 168-172(1957)

. 74. Lacroix P. Ca-45 autoradiography in the study of bone tissue. In: Bone as a tissue (Rodahl K, Nicolson JT, Brown EM, eds). NewYork:McGraw-Hill, 1960;262-279. 75. Scheiman-Tagger

E, Brodie AG. Leadacetate

as a marker

of growing

calcified tissues. Anat Rec 150:435440(1964). 76. Hong YC, Yen PK-J, Shaw JH. An analysis

of the growth of the cranial vault in rabbits

by vital staining

with lead acetate.

Calc Tiss Res 2:271-285(1968). 77. Yen PK-J,Shaw

JH. Remodeling

of compact bone studiedwith lead acetate as an intravital stain. J Dent Res 56:961-966(1977). 78. MacDonald NS, Ezmirlian F, Spain P, McArthur C. The ultimate site of skeletal deposition of strontium and lead. J Biol Chem 189:387-399(1951). 79. Verbeeck

RMH, Lassuyt

CJ, Heijligers

HJM, Driessens FCM, Vrolijk

JWGA. Lattice

parameters and cation distribution of solid solutions of calcium and lead hydroxyapatite. Calc Tiss Int 33:243-247(1981). 80. Bres EF, Voegel JC, Barry JC, Waddington, WG, Frank RM. Feasibility study for the detection of lead substitution sites in the hydroxyapatite

crystal structureusing highresolution electron microscopy (HREM) at optimum focus. J Appl Cryst 19: 168-173 (1986). 81. Miyake M, Ishigaki K, Suzuki T. Structure refinements

of Pb2+ ion-exchanged

apatites by
x-ray powder pattern-fitting. J Solid State Chem 61:230-235(1986). 82. Cohen N, Eisenbud M, Wrenn ME. The retention and distribution

of lead-210 in the adult baboon. Progress

report, Radioactivity studies. New York:New York University Medical Center, 1970. 83. LindhU, Brune

D, Nordberg

G. Microprobe analysis of lead in human femur by proton induced x-ray emission (PIXE). Sci Total Environ10:31-37(1978). 84. Hu H, Milder FL, Burger DE. X-ray

fluorescence:issuessurrounding the application

of a

new tool for measuring burden of lead. Environ Res 49:295-317(1989). 85. Jones KW, Schidlovsky G, Burger DE, Milder FL, Hu H. Distribution of lead in human bone. III. Synchrotron x-ray microscope measurements.

In: Advances

in in vivo body composition studies (Yasumura S, Harrison JE, McNeill KG, Woodhead AD, Dilmanian FA, eds). New York: Plenum Press,1990;281-286. 86. Schidlovsky G, Jones KW, Burger DE, Milder FL, Hu H. Distribution of lead in human bone. II. Protonmicroprobemeasurements. In: Advances

in in vivo body composition studies (Yasumura S, Harrison JE, McNeill KG, Woodhead

AD, Dilmanian

FA, eds). New York: Plenum Press, 1990;275- 280. 87. Rosen JF. Metabolic and cellular effects of

614 Environmental Health Perspectives

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC

All use subject to JSTOR Terms and ConditionsResearch Advances u Kinetic model for lead in humans

lead: a guide to lowlevel

lead toxicity in children.In: Dietary

and environmental

lead: human health effects (Mahaffey

KR, ed). New York:Elsevier,

1985; 157-185. 88. Silbergeld

EK, Schwartz J, Mahaffey

K. Lead and osteoporosis.

Mobilization

of leadfrom bone in postmenopausal

women. Environ Res 47:79-94(1988). 89. Pounds

JG, Long GJ, Rosen JF. Cellular

and molecular toxicity of leadin bone.Environ Health Perspect 91: 17-32(1991)

. 90. Anderson

C, Danylchuk

KD. The effect

of chronic low level lead intoxication on the haversian remodeling

system in dogs. Lab Invest 37:466-469(1977). 91. Leggett

RW. A generic age-specific

biokinetic model for calcium-like

elements. Radiat Prot Dosim 41: 183-198(1992). 92. International

Commission

on Radiological Protection.

Alkaline earthmetabolism

in adultman. ICRP

Publication

20. Oxford: Pergamon Press, 1973. 93. Flood PR, Schmidt PF, Wesenberg GR, GadeholtH. The distribution of lead in human hemopoietic

tissue and spongy

bone after lead poisoning andCa-EDTA

chelation therapy. Arch Toxicol 62:295-300(1988). 94. Lloyd Rt), Mays CW, Atherton DR, Bruenger FW. Distribution

and retention

of injected Pb-210 in the beagle.

University of Utah College

of Medicine,

CO0-241. Salt Lake City, UT:University

of Utah, 1970; 105-122. 95. Rabinowitz

MB. Toxicokinetics

of bone lead. Environ Health Perspect 91:33-37(1991). 96. Castellino

N. Autoradiographic

research on the distribution

of Pb-210 in rat bone tissue. Folia Medica 50:11g125(1967). 97. Leggett

RW, Eckerman

KF, Williams

LR. Strontium-90

in bone: a casestudy

in agedependent dosimetric modeling. Health Phys 43:307-322(1982)

. 98. Holtzman

RB. Critique

on the half-lives

of lead and RaD in the human body. Report ANL-6297,

1961 ;67-80. 99. Holtzman

RB, Lucas HF, Ilcewicz

FH. The concentration

of lead in human bone.ANL7615. Chicago:Argonne

National Laboratory, 1969;43A9- 100. Holtzman RB. Sources of Pb-210 in uranium miners. Health Phys 18: 105-112(1970)

. 101. Jaworowski

Z. Stable andradioactive

lad in environment

and human body. Warsaw: Nuclear Energy Information

Center, 1967. 102. Black SC, Archer VE, Dixon WC, Saccomanno

G. Correlation

of radiation exposure and Pb-210 in uranium

miners. Health Phys 14:81-93(1968). 103.Smith FA, Hursh JB. Bone storage and release. In: Handbook

of physiology,

section 9. Reactions

to environmental

agents (Lee HK, ed). Bethesda,

MD:American

Physiological Society, 1977;469482. 104.Ahlgren

L, Haeger-Aronsen

B, Mattsson

S, Schutz A. In-vivo determination

of lead in the skeleton after occupational

exposure to lead. BrJ IndMed37:109-113(1980). 105.Steenhout

A. Kinetics

of lead storage in teeth and bones: An epidemiologic

approach. Arch Environ Health 37:224-230(1982). 106. Skerfving S, Christoffersson

J-O, Schutz

A, Welinder H, Spang G, Ahlgren

L, Mattsson S. Biological

monitoring,

by in vivo XRF rneasurements,

of occupational

exposure to lead, calcium, and mercury. Biol Trace Elem Res 13:241-251(1987). 107. Cohen N, Laurer

GR, PomroyC, Morse RS, Hickman DP, Estrada

JS, Neton JW. Longterm retention of 210Pb in man: a unique case of internal contamination. Health Phys 62:553-555(1992). 108.Christoffersson

JO, Ahlgren

L, Schutz A, Skerfving S, Mattsson

S. Decrease

of skeletal lead levels in man after end of occupational exposure. Arch Environ

Health 41:312- 318(1986). 109. Blanchard RL, Moore JB. Pb-210 and Po-210 in tissues of some Alaskan residents as related to consumption

of caribou or reindeer

meat. Health Phys 18: 127-134(1970). 110. Blanchard RL, Moore JB. Body burden,distribution and internal dose of Pb-210 andPo210 in a uranium

miner population.

Health Phys 21:499-518(1971). 111. Hamilton EI, Minski MJ, Cleary JJ. Theconcentration and distribution

of some stableelements in healthy

human tissues from the United Kingdom. Sci Total Environ 1:341- 374(1972). 112. Gross SB, Pfitzer EA, Yeager DW, Kehoe

RA. Lead in human tissues. Toxicol ApplPharmacol 32:638451

(1975). 113. Barry PSI. A comparison

of concentrations

of lead in human tissues. Br J Ind Med 32:119- 139(1975) 114. Barry PSI. Concentrations

of lead in tissues of children. BrJ Ind Med 38:61-71(1981). 115. Iyengar V, Woittiez

J. Traceelements

in human clinical specimens: Evaluation of literature data to identify

reference values. Clin Chem 34:47/f 481 (1988)

. 116. Ishihara N, Matsushiro

T. Biliary and urinary excretion of metals in humans.

Arch Environ Health 41:324-330(1986)

. 117.Klaassen

CD, Watkins

JB. Mechanisms

of bile formation,

hepatic uptake, and biliary excretion. Pharmacol Rev 36: 1-67(1984). 118. Morgan A, Holmes

A, Evans JC. Retention, distribution,

andexcretion

of lead by the rat afterintravenous

injection. Br J Ind Med 34:37-42(1977). 119. Victery W, Vander

AJ, Mouw DR. Effect

of acid-base status on renal excretion andaccumulationof lead in dogs and rats. Am J Physiol 237:F398-F407(1979). 120. Keller CA, Doherty

RA. Distribution

and excretion of lead in young andadult female mice. Environ Res 21:217-228(1980). 121. Victery W, Vander

AJ, Mouw DR. Renal handling of lead in dogs, stop-flow analysis. AmJPhysiol

237:F408-F414(1979). 122. Grandjean P. Regional

distribution

of lead in human brains. Toxicol Lett 2:65-69(1978). 123. Bryce-Smith

D, Stephens

R. Sources

and effects of environmental

lead. In: Traceelements in health (Rose J, ed). London: Butterworths,

1983;83-131. 124. Petit TL, Alfano

DP, LeBoutillier

JC. Early lead exposure and thehippocampus,

a review and recentadvances.

Neurotoxicology

4: 79_94(1983) 125. Niyogi SK. Tissue distribution

of lead in cases of poisoning

in children.

Forensic Sci 3:199- 202(1974). 126. Berman E. Toxic metals

and their analysis. London:Heyden,

1980. 127. Potter GD, McIntyre

DR, Vattuone

GM. The fate andimplications

of 203Pb ingestion in a dairy cow and a calf. Health

Phys 20: 650-653(1971). 128. Gross SB. Human

oral andinhalation

exposuresto lead: summary

of Kehoebalance experiments.

J Toxicol Environ Health 8:333-377(1

981). 129. Wielopolski

L, Ellis KJ, Vaswani AN, Cohn SH,Greenberg A, Puschett

JB, Parkinson DK, Fetterolf L)E, Landrigan PJ. In vivo bone lead measurements:

a rapid monitoring

method for cumulative

lead exposure.

Am J Ind Med 9:221-226(1986). 130. Somervaille

LJ, Chettle DR, Scott MC, Tennant DR, McKiernan

MJ, Skilbeck

A, Trethowan

WN. In vivotibia

leadmeasurements as an index

of cumulative

exposure in occupationally

exposed subjects. Br J Ind Med 45:174-181(1988). 131. Koster J, Erhardt A, Stoeppler

M, Mohl C, Ritz E. Mobilizable

lead in patients

with chronic renal failure. Eur J Clin Invest 19:228-233(1989). 132. Schutz A, Skerfving

S. Effect of a short, heavy exposure to lead dust upon blood lead level, erythrocyte

Saminolevulinic

acid dehydratase activityand urinary

excretion of lead, 6- aminolevulinic

acid and coproporphyrin. Results of a 6-month

follow-up of two male sub jects. Scand

J Work Environ Health 3:176-184(1976). 133.Cooper

WC, Tabershaw

IR, Nelson KW. Laboratory studies of workers in lead smelting and refining. In: Environmental

health aspects oflead: proceedings

of aninternational

symposium of the Commission

of the European Communities and the USEPA held in Amsterdam,

October 2-6, 1972. Luxembourg:Commission

of the European

Communities, 1973;517-530. 134. Skerfving S, Ahlgren

L, Christoffersson

J-O, Haeger-Aronsen

B, Mattsson

S, Schutz A, Lindberg G. Metabolism

of inorganic

lead in

man. Nutr Res (suppl 1): S601-S607(1985). 135. Shiels DO. The elimination

of lead in sweat. Aust Ann Med 3:225-229(1954). 136. Hohnadel DC, Sunderman

FW, Nechay MW, McNeely MD. Atomic

absorptionspectrometry of nickel,

copper, zinc, and lead in sweat collected from healthy subjects during sauna bathing. Clin Chem 19: 1288- 1292 (1973)

. 137. Stauber JL, Florence TM. A comparative

study of copper, lead, calcium andzinc in human sweat and blood. Sci Total Environ 74:235-247(1988). 138. Omokhodian

FO, Crockford

GW. Lead

in sweat andits relation

to salivary andurinary levels in normal healthy subjects. Sci Total Environ 103:119122(1991). 139. Omokhodian

FO, Howard JM. Sweat leadlevelsin persons

with high blood lead levels: lead in sweat of leadworkers

in the tropics.

Sci Total Environ 103:123-128(1991). 140. Vellar OD. Studies

on sweat losses of nutrients (dissertation).

Oslo, Norway:University

of Oslo, 1969. 141. Kopito L, Byers RK, Shwachman

H. Lead in hair ofchildren with chronic lead poisoning. N EngJ Med 276:949-953(1967). 142. Hammer DI, Finklea

JF, Hendricks

RH, Hinners TA,Riggan

WB, Shy C. Trace metals in human hair as a simple pidemiologic

monitor of environmental

exposure. In: Proceedings of the fifth

conference on trace substances in environmental

health(Hemphill

DD, ed). Columbia, MO:University

of Missouri

Press, 1971;25-38. 143. Paschal DC, DiPietro

ES, Phillips DL,Gunter EW.Age dependence

of metals in hair in a selected U.S. population. Environ Res 48:17-28(1989). 144. Wilhelm M, Hafner D, Lombeck

I, Ohnesorge FK. Monitoring

ofcadmium,

copper, lead, and zinc status

in young children using toenails: comparison

with scalp hair. Sci Total Environ 103:199-207(1991).

615 Volume 101, Number7, December 1993

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC

All use subject to JSTOR Terms and ConditionsResearch Advances @ Leggett

145.Clarkson

TW, Kench

JE. Uptake

of lead by human erythrocytes

in vitro. Biochem

J 69:432-439(1958). 146. Bruenger FW, Stevens W, Stover BJ. Theassociation of Pb-210 nvith constituents

of erythrocytes. Health Phys 25:37-42(1973). 147. Wetmur JG, Lehnert

G, Desnick

RJ. The 6- aminolevulinate

dehydratase

polymorphism: higher blood lead levels in lead workers and environmentally

exposed children with the 1-2. and 2-2 isozymes.EnvironRes 56:109- 1 19(1991). 148. Meredith PA, MooreMR, Campbell BC, Thompson

GG, Goldberg

A. Delta-aminolaevulinic acid metabolism

in normal andleadexposed humans. Toxicology 9:1-9(1978). 149.Kehoe

RK Themetabolism

of lead in man in health and disease. J R Inst Public Health Hyg 24:81-143(1961). 150. Griffin TB, Coulston

F, Wills H, Russell JC. Clinical studies on men continuously

exposed to airborne

particulate

lead. Environmental quality and safety, supplement

vol II (Coulston F, KorteF, Klein W, Rosenblum I, eds). Stuttgart:Georg

Thieme, 1975;221-240. 151.Cools A, Salle HJA, Verberk MM, Zielhuis RL. Biochemical

response ofmale volunteersingestinginorganic

lead for 49 days. Int Arch Occup Environ Health 38:129-139(1976). 152. Momcilovic

B, Kostial

K. Kinetics

of lead retention and distribution

i suckling and adult rats. Environ Res 8:214-220(1974). 153. Kello D, Kostial K, Harrison

GE. Influence of age and temperature

of incineration

on the loss of lead from rat bone. Health Phys 28: 169-170(1975). 154. Jugo S, Maljkovic

T, Kostial K. The effect

of chelating agents on lead excretion in rats in relation to age. Environ Res 10:271-279

(1975). 155. Jugo S. Chelatable

fraaion of Pb-203 in blood of young and adult rats. Environ Res 21:336-342(1980). 156. Pounds JG, Marlar

RJ, Allen JR Metabolism of lead-210

in juvenile and adult rhesusmonkeys (Macaca mulatta). Bull Environ Contam Toxicol 19:684-691(1978). 157. Kostial K, Kello D, Jugo S, Rabar I, Maljkovic T. Influence

of age on metal metabolism

and toxicity. Environ Health Perspect 25:81-86(1978). 158. Harley NH, Kneip

TH. An integrated

metabolic model for lead in humans ofall ages. Final report o theU.S. EPA,

contract no. B44899. New York:New

York University

School of Medicine, 1985. 159. Tipton IH, Cook MJ. Trace elements in human tissue. Part II.Adult subjects from the United States. Health Phys 9:103-145(1963). 160. Tipton IH, Shafer 

### n. Trace elements in human tissue: rib and vertebra. Health Physics Division Annual Progress Report for period ending July 31, 1964,ORNL-3697.

Oak Ridge TN:Oak Ridge National Laboratory,

1964. 161. Schroeder HA,Tipton

IH. The human

body burden

of lead. ArchEnviron

Health 17: 965-978(1968). 162. Troster EJ, Schvartsman

S. Lead exposure in pregnant women and their newborns in the city of Sao Paulo, Brazil. Biomed Environ Sci 1:64-70(1988). 163. Ryu JE, Ziegler

EE, Nelson

SE, Fomon

SJ. Dietary intake of lead and blood leadconcentrationin earlyinfancy.

Am J Dis Child 137:886-891

(1983). 164. Mehani S. Lead retention by the lungs of lead-exposed

workers. Ann Occup Hyg 9:165-171(1966). 165. Jacobi W. Thedose

to thehuman

respiratory tract by inhalation

of short-lived

Rn-222 and Rn-220 decayproducts.

Health Phys 10: 1163-1174(1964). 166. Waldron HA, Stofen

D, eds. Lead

metabolism. In: Subclinical

lead poisoning. London: Academic Press, 1974;38-76. 167. Bianco A, Gibb FR,Morrow

PE. Inhalation study of a submicron

size lead-212

aerosol. In: Proceedings

of thethird

international

congress of the IRPA.

CONF-730907-P2.

Oak Ridge, TN:U.S. Atomic Energy Commission, 1973;1214-1219. 168.CorazziariE, Cucchiara S, Staiano A, Romaniello

G, Tamburrini

O, Torsoli

A, Auricchio S. Gastrointestinal

transit ime,frequency of defecation,

and anorectalmanometry in healthy

and constipated

children. J Pediat 106:379-382(1985). 169. Jugo S, KelloD. Resorption of lead compounds from peritoneal cavity in rats. Health Phys 28:617-618(1975). 170.Conrad

ME,Barton

JC. Factors

affecting the absorption

and excretion

of leadin the rat. Gastroenterology

74:731 -740(1978)

. 171. Mahaffey KR. Nutrient-lead

interactions.

In: Lead toxicity (Singhal RL, Thomas JA,eds). Baltimore: Urban andSchwarzenberg,

1980; 425-502. 172. Anders E, Bagnell CR, Krigman MR, Mushak P. Influence

of dietary proteincomposition on lead absorption in rats. Bull Environ Contam Toxicol 28:61-67(1982). 173. Heard MJ, Chamberlain

AC.Effect of mineralsand foodon uptake

of lead from the gastrointestinal

tract in humans.

Hum Toxicol 1:411-415(1982). 174. Morton AP, Partridge S, Blair JA. Theintestinal uptake of lead. Chem Br 21:923- 927(1985). 175. Holt AC, Partridge

S, Morton AP, Blair JA. The intestinal

absorption of lead: the importance of lead speciation. In: Heavy metals in the environment, vol 2 (Lindberg SE, Hutchinson

TC, eds). Oak Ridge,

TN:Oak Ridge National Laboratory,

1987;375-377. 176. Harrison GE, Carr TEF, Sutton A, Humphreys

ER,Rundo

J. Effects of alginate

on the absorption

of Pb in man. Nature 224:1115-1116(1969). 177.Rabinowitz

MB, Kopple

JD, Wetherill

GW. Effect

of food intake and fasting on gastrointestinal lead absorption in humans.

Am J Clin Nutr 33:1784-1788(1980). 178. Chamberlain

AC, Clough

WS, Heard

MJ, Newton H, Stott ANB, Wells AC.Uptake

of lead by inhalation

of motor exhaust. Proc R Soc London B 192:77-110(1975). 179. Flanagan PR, Chamberlain

MJ, Valberg LS. The relationship

between iron and lead absorptionin humans.Am J Clin Nutr 36:823-829(1982). 180. James HM, Hilburn

ME,Blair JA. Effects of meals and meal times on uptake of lead from the gastrointestinal

tract in humans.

Hum Toxicol 4:401-407(1985). 181. Blake KCH. Absorption

of Pb-203 fromgastrointestinal tract of man. Environ Res 11: 14(1976). 182. Kehoe RA. Studies of lead administration

ad elimination

in adult volunteers under natural and experimentally

induced conditions

over extended periods of time.FoodChem

Toxicol 25:425494(1987). 183. Thompson

JA. Balance

between intake and output of lead in normal individuals.

Br J Ind Med 27: 189-194(1970). 184. Karhausen

L. Intestinal

leadabsorption.

In: Environmental

health aspects of lead, Proceedings of aninternational

symposium

of the Commission

of the European

Communities and the U.S. EPA

heldin Amsterdam,

October 2-6, 1972.

Luxembourg:Commission

of the European Communities,

1973;427-440. 185. Alexander

FW, ClaytonBE, Delves HT. Mineral andtrace-metal

balances in children receiving normal and synthetic diets. QJ Med 169:89-111(1974). 186. Alexander FW, Delves HT, Clayton

BE. The uptake andexcretion

by children

of lead and other contaminants.

In: Environmental

health aspects of lead, proceedings

of an international symposium

of the Commission

of the European Communities

and the U.S. EPA, held in Amsterdam,

October2-6, 1972. Luxembourg:Commission

of the European Communities,

1973;319-331. 187. Ziegler EE, Edwards BB, Jensen RL, Mahaffey KR, FomonSJ.Absorption and retention of lead by infants. Pediatr Res 12:29-34(1978). 188. Barltrop D, Strehlow

CD. The absorption

of lead by children.

In:Proceedings

of the third international

symposium

on trace metal metabolism

in man and animals (Kirchgessner M, ed). Munich:Technische University, 1989;332-334. 189. Forbes GB, Reina

JC. Effect

of age on gastrointestinal

absorption (Fe, Sr, Pb) in therat. J Nutr102:647452(1972). 190. Quarterman

J, Morrison

E. The effect

of age
on the absorption

and excretion

of lead. Environ Res17: 78-83(1978).

616 Environmental Health Perspectives

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:07:32 UTC

All use subject to JSTOR Terms and Conditions