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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)

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This work was initiated under the Radon Research 

Program, U. S. Department of Energy, Office of 

Health and Environmental Research, under contract 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 

result in subtle, adverse health effects, particularly in children. Consequently, there 

have been increased efforts by health protection agencies to develop credible, versatile 

methods for relating levels of lead in environmental media to levels in blood and tiSsues of 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 radiation doses from environmentally 

important radionuclides, induding radioisotopes of lead. This paper describes a new 

age-specific biokinetic model for lead onginally developed for the ICRP but expanded 

to indude additional features that are usefill 

for consideration of lead as a chemical toxin. 

The model is developed within a generic, 

physiologically motivated framework designed tO address a class of calciumlike elements. This framework provides a useful 

setting in wlwich to synthesize experimental, 

occupational, and environmental data on 

lead and exploit common physiological 

properties of lead and the aLkaline earth elements. The modular design is intended to 

allow researchers to modify specific parameter values or 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 

red blood cell lead is modeled for concentrations above that level. The model is shown 

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

experimental and natural conditions. Key 

words: age-specific metabolism, biokinetics, 

kinetic model, lead. Environ Hcalth Perspea 

101:598 616(1993) 

Despite an overall decrease in human exposure 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, elevated gastrointestinal absorption of lead, elevated turnover of 

bone lead into blood, and incompletely 

developed organs and defense mechanisms. 

The growing awareness of the health 

threat posed by lead has stimulated increased efforts tO develop a detailed characterization of the biological behavior of lead 

in humans of all ages. Several biokinetic 

models for lead have now been published 

(8-20). Most of these were derived as 

curve fits to limited data from controlled 

metabolic studies on adult human volunteers or laboratory animals at different 

stages of life. In some cases an attempt has 

been made to improve upon 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 have been developed within one of 

two generic model structures. One of these 

applies to the "bone-surface-seeking" ele- 

* . . . . ments, lnc uc lng 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 aworkable 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 paper are to 

explain the conceptual basis of the lead 

model as developed for the ICRP and 

expand that model to include features that 

are useful for consideration of lead as a 

chemical toxin but that are unimportant 

for consideration oflead as a radiological 

toxin. In contrasto the version of this 

model developed for the ICRP, the expanded version includes a relatively detailed description ofcirculating lead, a concentration-dependent transfer rate into red 

blood cells (provided the lead concentration in red blood cells exceeds a specified 

threshold level), and consideration ofthe 

brain as a separate compartment. 

Brief Ovennew 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 the translocation of lead from the respiratory orgastrointestinal tract into blood. The respiratory and gastrointestinal models used in 

the present paper to evaluate human exposure 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 compartments used in the systemic model and 

directions of movement of lead among 

these compartments is given in Figure 1. A 

more detailed schematic diagram of the circulation, i.e., the model for lead in blood 

and rapidly exchanging extravascular fluids, 

. . . . 

1S S. lown sn qlgure w. 

Transport of lead between 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 areincreased 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 

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Research 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 Lead that 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 plasma compartment. For example, a deposition fraction of 

0.24 is assigned tO RBCS. This means that 

24% of the lead atoms leaving plasma in a 

short time (seconds) are assigned to the 

RBCs compartment. Since the total transfer 

rate from diffusible plasma to all destinations combined is estimated as 2000/day, 

the transfer rate from diffusible plasma to 

RBCs is 0.24 x (2000/day) = 480/day. The 

use of deposition fractions provides one way 

of introducing consideration of material balance and competition between 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 compartment other 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 EVF is assigned a deposition fraction of 0.5 and thus receives about half of 

the injected amount within minutes. This 

initial inflow into EVF rapidly redistributes 

to the other compartments, virtually doubling 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 model of the circulation, which is shown in more detail in hgure 2. 

competition from the RBCs, but firstorder transport between all other compartments 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 the six age groups 

considered in Publication 56 of the International Commission on Radiological 

Protection (21,22. Transfer rates for ages 

intermediate to those addressed inTable 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 

plus 0.75 times the rate given for age 5 

years. Changes with age in the biokinetics 

of lead during adulthood are not addressed 

here, but variation with adult age in the 

rate of bone turnover, in particular, can 

easily be induded in the model if desired 

(23,24. 

Several software packages are available 

for solving the 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 the biological half-time 

that one would observe, theoretically, if OUtflow 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 the outside observer isa 

few weeks 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 per unit time 

from one compartment toanother. (Note 

that the transfer 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 of transfer rates from 

that compartment toall destinations. For 

example, the total transferate from diffusible plasma to all other compartments is 

estimated as 2000/day, which corresponds 

to a removal half-time from diffusible plasma of In(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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Table 1. Age-specific transfer rates (per day} for the model indicated in Figures l 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 0.25 times 

the rate given for age 1 year plus 0.75 bmes the rate given for age S years. 

bPlasma-D and plasma-B are diffusible and bound plasma compartments; trab and cort indicate trabecular 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 from urinary bladder to urine. 

dThere is also assumed transfer from 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 at 2000/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 high affinity for lead and contain nearly all of the 

blood lead (BPb) under most conditions. 

The blood concentration increases approximately linearly with intake at relatively 

low levels of intake but increases more 

slowly with high levels of intake (17,18, 

35). It has been found that the fraction of 

BPb associated with plasma increases at 

blood lead concentrations substantially 

exceeding 25 pg/dl, and that there is also a 

nonlinearelation between lead in blood 

and that in urine, bone, and other tissues 

and fluids at such levels (17,36L38). As 

discussed later, such nonlinear behavior of 

lead at high levels of intake may result 

largely from a reduced rate of flow from 

plasma into RBCs as certain lead-binding 

components of these cells become saturatE gWtW : 

, }r j.i,F ,1 0 , 

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 path to 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 the total outflow 

from diffusible plasma is assigned to a protein-bound compartment of plasma that 

returns lead slowly to diffusible plasmand 

eventually contains most of the plasma 

lead. 

Total transfer rate fi rom dif siblu plusma (to all destindtions). Immediately after 

intravenous injection of radiolead into 

adult humans, 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). The assigned transfer rate of 

lead from diffusible plasma to all destinations should be somewhat higher than 

1/min, however, to account for rapid 

uptake by RBCs (Fig. 3) as well as transfer 

E XDEI^kIl.Iu ¢1 1- iilKl 

B ht1 !%1t 1 gw ,| | 

ar ' X ' M 

t1 , S i , , + - l w iw 

5 lo loo looo 

Minutes after Inhalation 

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 human subjects by intravenous 

injection or inhalation. 

600 Environmental Health Perspectives 

Model for Adults 

Cirnllation 

Basis for two plasma comparanents. Soon 

after introduction of a lead tracer (radiolead) into blood plasma, the tracer is 

largely available for diffusion into extravascular fluids and filtration by the kidneys 

(2a28). Under steady-state conditions, 

however, most of the plasma lead apparently 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 of plasma lead tO nondiffusible plasma proteins (Fig. 2). Lead 

injected or absorbed into blood or returning to blood from the extravascular spaces 

is assigned to the diffusible compartment 

within plasma, from which it transfers 

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Research Advances @ Kinetic moclel for leacJ in hesmans 

ed. At least one of these components may 

present amovlng 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 

detailed process model of uptake and 

retention of lead by RBCs would require 

several compartments, with some being 

saturable and at least one having an exposure-dependent saturation level. At pre- 

- 

Xo *_Xillil 

X _ _iS]]: , _ 

W_-v S l _ w5 m _]X w i ws | S wo_ 

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

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

9 w_ti=Xb I _ 

05 1 10 100 1000 

Minutes atter Injection 

Figure 4. 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 adult human subjects. 

z | | | | S . l 

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

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 __ 

a ___e___a_ 

e _|S1 _9gS 

n _ 11 __i_| 

_ _BiL1L_}L 

R _R | W li -l 

_s_3s_|_|_gw__ 

O | 16 24 w Z Z 56 64 n " 

Hours a*0r End ot Inhalation 

Figure 5. 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 

this model the RBCs are represented asa 

single compartment inexchange with diffusible plasma, but nonlinear kinetics is 

imposed at relatively high concentrations 

of lead in RBCs. That is, above a threshold 

concentrationf lead in RBCs, the transfer 

rate from plasma to RBCs is assumed to 

decrease as the concentration of lead in 

RBCs increases. 

Trangerates benveen dif sible pl=- 

ma and RBG. A minimum blood content 

of about one-third of the injected amount 

is reached within 2-3 min (Fig. 4), at 

which time roughly three-fourths ofBPb 

resides in RBCs (Fig. 3). The RBC content 

then increases over a period of hours as 

most of 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% 

of the injected or absorbed amount (Figs. 4 

and 5) 27,28,31,32,41-45). Over the next 

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 and sizable intersubject variability are apparent at 

times remote from exposure, when the 

blood content may be determizned as much 

by the rate of feedback from bone and soft 

tissues as by the rate of loss from RBCs. 

10 _||__|lAvailable data on retention of tracer 

lead in blood of human subjects can be 

reproduced reasonably well by assuming 

that the RBCs receive about a fourth of the 

lead atoms leaving diffusible plasma (more 

precisely, adeposition 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 lead in 

RBCs, the transfer rate from diffusible 

plasma to RBCs is 0.24 x (2000/day) = 

480/day. As described later, the deposition 

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 

of plasma lead is not known, but it appears 

to be considerably larger than the diffilsible 

fraction under steady-state conditions 

(26,29,30,37,48). After parameter values 

for diffusible plasmand RBCs are set, reasonablestimates of the transfer rate from 

diffusible plasma to protein-bound plasma 

and of the removal half-time from proteinbound 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 and plasma, and 3) the ultrafilterable fraction of plasma lead. 

Data on healthy human subjects receiving radiolead by injection or inhalation 

6_ § " _om 

rm2 ffi SubjK B0 [ 

> l_-| u--15 

; __=1" 

cs ___ _ 

t e____ 

- 3 =z__ a ____ __FW__ __ 

X - ___ 

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

o 

o 

o 

o 

- 

O !R1 100 150 200 250 300 

Days atter Beginning of Intake 

50 100 150 2|0 

Days aft0r Beginning of Intake 

o ul 

.= 11 

a z 

.> 

| 

o 

o 

- 

g 

iL 

a 

0 2 4 6 8 10 12 14 16 

Davs after Injection 

O 50 1W 150 2W 250 

Davs after Beginning of Intake Days after Beginning 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. 

Predictions and 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 adult human subjects as a function of time after beginning of controlled 

ingestion of an isotope of lead. Ingestion periods for 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 after the initial intake. 

The gastrointestinal absorption fractions assuwed for subjects A, B, D, and E were 0.10, 0.07, 0.12, and 

0.09, respectively, as derived by Rabinowitz and co-workers (99 and adjusted by Chamberlain et al. (27). 

Volume 101, Number 7, December 1993 

601 

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Research Advances @ Leggett 

indicate that the RBCs contain 95-99% of 

the blood content of radiolead at 0.5-1 hr 

after injection (31,33), more than 99% at 

3 hr after injection (31), more than 99.5% 

at 10 hr or more after injection or inhalation (27), and about 99.8% at 50-100 hr 

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 reasonably consistent with modern data on laboratory animals. For example, more than 99% of 

2l0Pb in blood was associated with RBCs 

by 1 hr after injection of this isotot)e into 

beagles (49); about 99.8% of 2ltPb in 

blood was found in RBCs of adult monkeys at 96 hr after oral intake of this isotope (50); and nearly 99.8% of 2l0Pb in 

blood was associated with RBCs by 1 day 

after injection into rabbits (51). In rats, 

plasma may contain as much as 2% of 

BPb, even at low blood lead levels (20,5X. 

The division of lead between RBCs 

and plasma of chronically exposed humans 

or laboratory animals has not been clearly 

established, mainly because of the difficulty in measuring the typically low concentration in plasma and the possibility of 

cross-contamination from RBCs (27,53). 

Another complicating factor is that (as discussed later) there is a nonlinear relationship between the plasma lead and blood 

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, but more recent estimates are in 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 contain roughly 

1-2% of blood lead for a wide range of 

exposure levels. Measurements of Everson 

and Patterson (56;) suggest that plasma 

contained only about 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 plasma contains roughly 0.2% of BPb at an equilibrium blood lead concentration of10 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 exposures indicate that plasma may contain roughly 

0.1% of BPb. The present model is designed to yield an equilibrium plasma lead 

content of 0.2% of BPb for low levels of 

lead intake (but higher percentages for elevated intakes), since this value is suggested 

by studies on humans administered radiolead and is reasonably consistent with 

recent measurements of stable lead 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 with renal 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. 

Transferates between diffusible and 

bound plasma lead were set for agreement 

with 1) data on the early division of radiolead between plasmand RBCs, 2) experimental determinations ofurinary clearance of plasma lead (discussed later), 3) the 

estimate that plasma lead represents 0.2% 

of BPb at equilibrium, and 4) the estimate 

that 15% of plasma 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. The assigned removal halftime from bound to diffusible plasma is 5 

days, which is of the same order as the 

half-life of plasma 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 gradient within a few minutes and brings back a substantial portion of extravascular lead to 

blood (28,31,40,41). Compartment EVF 

is used to model this rapid feedback of lead 

from extravascular spaces. This compartment is assumed to exchange lead only 

with diffusible plasma. Lead that moves 

from plasma to extravascular fluids to 

retention sites in tissues is treated as if it 

passed directly from plasma to those retention 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 transferates for other 

compartments. 

Tranefer rates benveen diffiusible plusma 

and EVF. The deposition fraction for EVF 

is set at 0.5 to reproduce the early rapid 

return of lead tO plasma from the extravascular spaces. Thus, the transfer rate from diffusible 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 as great, or 333.3/day; this is derived 

from the postulate that the EVF compartment contains three times as much lead as 

diffusible plasma at equilibrium, which is 

suggested by kinetic analysis of plasma disappearance curves for isotopes of the alkaline earth elements. For example, Hart and 

Spencer (34) estimated from measurements on humans injected with radiocalcium that the volume of the rapidly exchanging extravascular fluids is about 3 

(2.4 4.5) times the volume of the plasma 

pool. Similarly, Harrison and co-workers 

(5Q) concluded from measurements on an 

adult male subject that intravenously 

injected radioisotopes of calcium, strontium, barium, and radium were rapidly 

dispersed into an extravascular pool about 

three to four times the size of plasma. 

Bone 

Similurgiies benveen lead and the alkaline 

earth elements in bone. It has been recognized for many years that lead follows the 

movement of calcium in the body to 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 has been found that 

lead competes with calcium for deposition 

in bone and distributes similarly to calcium and other alkaline earth elements 

among different bones and between trabecular and cortical bone structures (49,6S 

62,6n. Bone lead may remain more mobile than bone calcium for some time after 

deposition (66,67), but data on humans 

and laboratory animals indicate that longterm skeletal distribution and retention are 

similar for lead and the alkaline earth elements (49,68-71). In human cadavers, the 

lead concentration was closely 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 as a marker 

of bone growth and osteon formation, and 

a close resemblance in the patterns of 

deposition of lead and calcium in forming 

osteons has been 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 bone formation has been observed, and there is evidence that lead is 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 cellular lead in bone is rapidly exchangeable 

and is modulated by the same ions and 

hormones that regulate bone calcium 

metabolism (87-8S). However, high concentrations oflead in bone leads to damage 

to bone cells and interference with bone 

remodeling (9Gt). 

602 Environmental Health Perspectives 

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Research Advances h Kinetic model for lead in humans 

Structure of the bone 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. 

The model structure is an updated version of the long-standing alkaline earth 

model for adult humans described inICRP 

Publication 20 (92. This new version has 

been adopted by the ICRP for consideration 

of the 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: cortical surface, cortical volunle, trabecular surface, and 

trabecular volume; 2) the rapidly exchangeable 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 

of resorption 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) the more 

slowly exchangeable material in bone is 

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

with bone resorption. In contrasto the 

ICRP's earlier model for alkaline earth elements: 1) redeposition of material removed 

from bone compartments is treated explicitly and 2) material is assumed to be removed 

from all bone compartments byfirst-order 

processes. 

The ICRP's earlier alkaline earth model 

is a catenary (non-recycling) model involving 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. 

This intermediate-term loss from bone is 

generally ascribed to "diffusion" of material 

into osteons and/or ionic exchange of a portion of the element in deep bone with shallow bone pools or plasma calcium and has 

been incorporated into some biokinetic 

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

.. . . . 

processes glvlng rlse to lntermec late-term 

loss from bone have not been clearly established, 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 process generally hypothesized and in part from other 

processes, such as turnover of lead-binding 

components ofthe organic matrix of bone 

(93) or gradual release of lead from cellular 

components ofbone. 

Whatever the processes, the existence 

of intermediate-term loss of lead from 

bone is 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 after exposure to lead (95), although itmust be considered that high concentrations oflead 

may have changed the kinetics of lead in 

bone. 

In the present model, cortical and trabecular bone volume are each viewed as 

consisting of two pools, referred tO as the 

exchangeable and nonexchangeable pools 

(Fig. 1). The exchangeable bone volume 

pool is identified with intermediate-term 

loss from bone, meaning loss not associated with rapid exchange with plasma or 

slow loss by bone resorption. Calciumlike 

elements moving from bone surfaces to 

bone volume are assumed to enter the 

exchangeable pool and to leave this pool 

with an 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 and part is assigned to the 

nonexchangeable bone volume, from 

which it is assumed to be removed to plasma only by bone resorption. The rate of 

removal from nonexchangeableone volume is equated with the rate of bone 

turnover and is independent of the calciumlikelement considered. The parameter 

values assigned to exchangeable bone volume and bone surfaces are assumed to 

include any effects of bone 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 bone surfaces and not 

plasma, and 3) all lead reaching bone volume is initially available for exchange are, 

at best, only partially accurate. The trilayered model of bone is intended only to 

approximate the net result of the various 

processes involved in the time-dependent 

uptake and removal of lead from 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 with blood but has varying 

degrees of accessibility until penetrating 

the crystal surface, after which it becomes 

firmly buried and must await osteoclastic 

turnover. 

Rates of uptake and loss by bone surfaces. The net rate of exchange between 

diffusible plasma and rapidly exchanging 

regions of bone (assumed to be at the bone 

surfaces) and the amount of lead initially 

retained in bone can be inferred from generally consistent data on healthy adult male 

humans (28), baboons (82), and beagles 

(49) injected with radiolead. These data 

indicate that the adult skeleton accumulates about 10-1 5% of intravenously 

injected lead within 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 over a period of weeks as lead 

returns from RBCs and soft tissues to plasma and accumulates in regions of bone 

with slower loss. By 34 weeks after injection, bone contains roughly 25% of the 

administered amount (Fig. 8). These data 

can be reproduced reasonably well if it is 

assumed that 1) the deposition fraction on 

all bone surfaces 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) 

lead is removed from each bone surface 

compartment at a rate of 1/day, with half 

of the removed lead returning to diffusible 

plasmand half migrating to sites in bone 

with longer retention (exchangeable bone 

volume). Thus, the transfer rate from trabecular or cortical bone surface to diffusible plasma is 0.5/day, and the transfer 

rate from trabecular or cortical bone surface to 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 ofradioactive lead 

in trabecular bone of dogs was at least five 

times higher than that in cortical bone 

r . . . , S . soon atter lnjectlon. nls seems conslstent 

with limited biopsy data on human sub- 

. . . . Jects lngestlng aeac lsotope tracer over a 

period of months (Table 2), when it 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 

of bone lead is likely to have occurred. 

The initial division of lead between trabecular and cortical bone appears to be 

similar to that of the alkaline earth elements [compare, for example, results of 

McLean et al. (62) for lead in dogs with 

results of Norrdin and Arnold (65) for calcium in dogs]. As assumed earlier for the 

alkaline earth elements (91,97), the rate of 

transfer of lead from diffusible plasma to 

trabecular and cortical bone surfaces is 

Volume 101, Number 7, December 1993 603 

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exposed tO lead, summarized in a later section, are consistent with the assumption 

that a 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 

from exchangeable 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 indicate that skeletal retention is similar for these elements, particularly after a few weeks, and that their rate 

of removal from the skeleton after a few 

months may be largely controlled by the 

rate of bone resorption (49,71). As in an 

earlier model 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 leaving nonexchangeable bone volume enters diffilsible 

plasma. The age-specific bone turnover 

rates given in Table 1 are those developed 

in an earlier paper (97) and adopted by the 

ICRP (21). These values are based on histomorphometric measurements on human 

subjects and studies of retention of certain 

bone-seeking radionudides in human subjects. Most histomorphometric measurements are on ribs and iliac crest, but there 

Table 2 Measurements and model predictions of 

the concentration {p9/9} of lead in biopsied iliac 

bone from human subjects ingesting a lead isotope tracer over a period of 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 

aData are 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 are no 

differences in turnover rates of cortical and 

trabecular bone early in life but that differences 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 turnoverate of lead 

in the adult human skeleton. Estimates 

have been based on animal studies, the rate 

of bone remodeling, balance considerations 

regarding 2l0Pb or stable lead, the dedine 

of BPb after the end of occupational exposure, and in vivo measurements of 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 kBq in 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 rate of 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 (see the section on excretion), the 

urinary excretion measurements (taken in 

1990) indicate a biological removal rate of 

0.021-0.023/year. The present model predicts that a total-body burden of 9.55 kBq 

of 2l0Pb remaining after an acute intake 33 

years earlier would decline tO 5.15 kBq 

after 10 more years, and that the biological 

removal rate from the total body at 43 

years would be 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 bone in 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 agreement between the estimated dedine of lead 

in finger bone and the dedine in blood of 

these subjects (106,108). Based on these 

_ r - 

= _ 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 humans are 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 Cohen et al. {(. 

assumed to be proportional tO the calcium 

addition rate of the given bone 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 from diffusible plasma to trabecular bone s&ces is 

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

88.9/day 

and the transfer rate from diffusible 

plasma to cortical bone s&ces is 

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

71.1/day. 

Rates of loss from the exchangeabk 

bone volume compartrn4nts. Parameter values for the exchangeable bone volume 

compartments are based on 1) data on 

retention of 210Pb in whole bodies and 

bones of 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 

few months. Data on humans chronically 

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Research Advances 2 Kinetic model for lead in humans 

data and additional measurements of lead 

in bone biopsies (vertebrae), blood, and 

urine of present or former lead workers, 

Skerfving et al. (106) concluded that the 

skeletalead pool is not kinetically homogeneous, that turnover of lead is faster in 

the mainly trabecular vertebrae than in 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 from the 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 realistic occupational exposure scenarios, the predicted 

dedine in total bone lead after the end of 

exposure corresponds tO a half-time on the 

order of 10-12 years during the first few 

years after exposure and roughly 25 years 

at 25-30 years after exposure. 

Liver: Model Seructure and Transfer 

Rates 

The liver and kidneys are treated separately 

from other soft tissues because of their 

importance as excretion pathways for lead 

and because they show substantially higher 

concentrations of lead than most soft tissues. 

Data on injected lead 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 adult humans, the liver may 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 lead from liver 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, quantitative information on biliary secretion of 

lead by laboratory animals (particularly 

rodents) is of limited value for present purposes. 

In this model the liver is viewed as con- 

. . P 

SlStlllg 0t two compartments. A compartment with relatively high uptake from 

plasmand a relatively short removal halftime (several days) is needed to help reproduce the pattern of uptake and decline of 

lead observed in human subjects, baboons, 

and beagles during the first few weeks after 

intravenous injection. An additional liver 

compartment with much smaller uptake 

but with gradual build-up of 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 are referred tO as liver 1 and 

liver 2. 

Available data on hepatic uptake and 

retention of lead in htumans and laboratory 

animals and on biliary secretion of lead in 

humarz can be reproduced reasonably well 

with this two-compartment model and the 

following assumptions: 1) of lead leaving diffusible plasma, 4% deposits in liver 1. Thus, 

the transfer rate from 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 longterm retention compartment (liver 2), 45% 

enters the contents of the small intestine via 

biliary secretion, and 45% returns to diffusible plasma. Thus, the transferate from 

liver 1 tO liver 2, for example, is 0.1 x 

0.693/(10 days) = 0.00693/day. Lead entering the contents of the small intestine in 

liver bile is assumed to follow the same 

kinetics as ingested lead (see appendix); 3) 

the removal half-time from liver 2 is 1 

year. All lead leaving liver 2 is assumed tO 

return tO diffusible plasma. 

Model predictions are reasonably consistent with data on chronically exposed 

adult humans indicating that the liver may 

contain roughly 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 Figure 9 with 

data on human subjects, baboons, and beagles injected with radiolead. The observations for human subjects indicated in 

Figure 9 are only semiquantitative estimates 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 first 1-2 hr, 

that the preponderance ofthe deposited 

activity represents filtered lead, and that a 

substantial portion of the early accumulation is reabsorbed orlost in urine within a 

few hours (118-120. In rats, the kidneys 

contained roughly 10% of the intravenously injected amount after 1 day but less than 

2% after 9 days (8X. In baboons receiving 

radiolead by intravenous injection, the kidneys contained roughly 4% of the administered amount after 1 day, 0.6% after 30 

days, and 0.1% after 60 days (82. Comparison of the dedine of renal and hepatic 

activity over the first tWO months in these 

baboons indicate ahalf-time in the kidneys 

that would be roughly one-half of that in 

the liver, if each of these organs were considered 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 two compartments, one with 

relatively high deposition but short retention of lead and one with relatively low 

uptake but long retention. These compartments are referred tOas the "urinary path" 

(UP) and "other kidney tissue" (OKT), 

respectively. Both are assumed to receive 

lead from diffusible plasma. Material 

removed from UP moves to the urinary 

bladder contents, and that removed from 

OKT returns to diffusible plasma. Compartment UP is needed to reproduce an 

early rapid buildup and fairly fast (days) 

decline of lead in the kidneys 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 OKT is needed to reprozs S * | f | 

- | | | . 

- -Mosbl PileboZs 

ZD --- H_"{Semi-quanitativeData) 

; _- I | | V 

* 1 ll 11E * Ihl 

_ IE " I 

s= AR 

.= WH B I _E __ 

a _[ ___W 3[__[__ 

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 Cohen et al. {82). 

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Research Advances 0 Leggett 

Brain: Model Structure and Transfer 

Rates 

The brain is considered explicitly in this 

model because of its high sensitivity to lead 

as a chemical toxin. Lead is distributed 

unevenly in the brain, with the distribution depending to some extent on the level 

of exposure. At low levels, the lead concentration in different regions of the human 

brain is significantly correlated with the 

. . . . . potasslum concentratlon, lnc ilcatlng tzat 

lead is mostly accumulated in cell-rich 

parts of the brain such as the 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 where calcium localizes (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 multiple compartments and consideration of nonlinear 

kinetics. Due to limitations in kinetic data, 

however, the brain is treated here as a single compartment that exchanges lead slowly with diffusible plasma, and linear kinet- 

. . 

lCS lS assumec . 

Data on baboons, dogs, and rodents 

indicate that the brain has low uptake but 

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

young adult female baboons intravenously 

injected with 210Pb, the brain contained 

about 0.04% of the administered 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% at 3-4 years. 

An assumed deposition fraction for 

brain of 0.00015 [corresponding to a 

transfer rate from diffusible plasma to 

brain of 0.00015 x (2000/day) = 0.3/day] 

and a removal half-time of 2 years yield 

predictions that are reasonably consistent 

with injection data for large laboratory animals and with autopsy data for occupationally as well as environmentally 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 of 0.15% at 6 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 ratios observed 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 

of the net result of these three processes. 

The parameter values for the UP compartment of the kidneys were based largely 

on the data for laboratory animals summarized above but were adjusted for consistency with time-dependent urinary excretion 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 or two after injection. 

It is assumed that 2% of lead leaving 

diffusible plasma deposits in the urinary 

path compartment, UP, yielding atransfer 

rate from diffusible plasma to UP of 0.02 

x (2000/day) = 40/day. The removal halftime from UP to the urinary bladder contents is assumed to be 5 days, corresponding to a transfer rate of 0.693/(5 days) = 

0.139/day. 

After the parameter values for the urinary path compartment were selected, 

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 OKT compartment receives 0.02% of lead leaving diffusible plasma (amounting toabout 1% of 

the total deposition in the kidneys). Thus, 

the transfer rate from diffusible plasma to 

OKT is 0.0002 x (2000/day) = 0.4/day. 

The removal half-time from OKT to diffusible plasma is assumed to be 1 year, corresponding toa transfer rate of 0.693/(365 

days) = 0.0019/day. 

The model predicts that the kidneys of 

the adult would 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. 

the body's mass but only a small percentage of 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 

that time (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 the other soft tissues are 

assumed to consist of three compartments, 

ST0, ST1, and ST2, representing a wide 

range of turnoverates. These compartments are based primarily on kinetic considerations and cannot be given precise 

anatomical definitions. 

Compartment ST0 is assigned ahigh 

turnover rate and, together with bone surfaces, accounts for most of the feedback 

from extravascular spaces to plasma occurring 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 day and considerations ofmass balance of the deposition fractions in different 

organs, it is assumed that ST0 receives 

almost 9% (precisely, 8.875% to achieve 

mass balance of deposition fractions) of 

lead leaving 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 ST0 to 

diffusible plasma is 0.693/(0.333 day) = 

2.08/day. 

In beagles injected with 2l0Pb, soft tissues other than liver, kidneys, and brain 

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 at 28 days was found in pelt. 

In this model, compartment ST1 is used to 

depict such intermediate-term loss (i.e., a 

few weeks or months) from other soft tissues and also serves as the source of loss of 

lead from the body in substances other 

than urine, feces, and sweat (e.g., hair, 

nails, and desquamated skin). The deposition fraction for ST1, the total removal 

half-time from ST1 to diffusible plasma 

and excreta, and the division of outflow 

between diffusible plasmand excreta were 

chosen for broad consistency with data on 

intermediate-term retention of lead in soft 

tissues of laboratory animals and data on 

the rate of loss of lead in hair, nails, and 

skin of human subjects (9?. It is assumed 

that ST1 receives 0.5% of lead leaving diffusible plasma. The total removal half-time 

from ST1 is assumed to be 100 days, with 

606 Environmental Health Perspectives 

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Research Advances @ Kinetic model for lead in humans 

60% of the outflow returning to diffusible 

plasma and 40% 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, the transfer rate from 

ST1 to diffusible plasma is 0.6 x 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 and is used to account for 

most of the lead in massive soft tissues of 

chronically exposed humans. To avoid a 

gross overestimate of data for beagles 

injected with 210Pb, it must be assumed 

that no more than 0.1% of the injected 

amount is deposited in a soft-tissue compartment with a retention time of years. 

Then, in order for compartment ST2 to 

gradually accumulate the level of lead indicated 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 ST2 receives 0.1% 

of outflow from diffusible plasma and 

returns lead to 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 the transfer 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. As with the liver 

and kidneys, the model was designed 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 four pathways: urinary excretion, fecal excretion, 

sweat, and all other excretion pathways 

combined (mainly hair, nails, and desquamated skin). It is assumed that a portion of 

lead entering the urinary bladder passes 

directly from diffusible plasma to the urinary bladder contents and the rest is 

released to the bladder contents after temporary retention in the renal tubules (compartment UP). Lead in feces is assumed to 

originate from two sources: biliary secretion 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 that the absorption fraction for 

lead entering the small intestine in liver 

; g g | | | | | | | E | lX 1 raRm 

s | | 0 | g || | | | | X | . 

1D DDl' 

. _ =E =S = 

n _= n_ =g 

.= EEEEXX 

@ @@@@|= ||= | 

e ==|== = 

W t1 = Q QQQX 

X X8 = 

- w____ 

@s 

" Xi = 

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

at Hours after Intake 

||||||l INHAL^noN | 

_ as B{a)X-7 

ffi 1|1_ v * {3z)"4 S _}=S *s Elt 

_ 0 _ _# v xev 

*- _ES_=El=w 

n --= 

_E_ _ 

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 

- ; {ingesting Pb W 

= =_ = S 

* _ = = SS 2aqP5 KZYPS _ = 

X 03_r_N= 

S - _ - - - - - - 

Q t2F 

X == = = 

Ul FQ = S--X= =El '' 

@ - =N = =S= 

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 rate of urinary excretion 

of radiolead at early times after administration to 

adult human subjects. Sources of data are indicated 

bile or other secretions ithe same as that 

for ingested lead. Lead is assumed to be 

transferred directly from diffusible plasma 

to sweat. Losses in hair, nails, and desquamated skin are represented as a transfer 

from soft tissue compartment ST1 to 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 the urlnary excretion 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 absorption to blood, superimposed onthe excretion curve for injected lead (Fig. 10). For 

comparison of model predictions with 

I 

observed urinary excretion rates in humans, it is assumed that the urinary bladder is emptied completely with each void- 

M 2 l i @ | 01 0 l E0F XUggas 5j« 

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

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

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

Days after Injection 

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: 

_ ggglllggg8>gg I nON ,'. >''4,8, 

ffi ffi 1gggElEENg- unne W AS.E 

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 

g 

ae «oSl@X!W0023200 

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

Days after Inhalation 

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 

point for 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 determined in {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 from the 

model or assume that removal from the 

urinary bladder contents to urine follows 

first-order kinetics; aremoval 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 first 24 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. 1 1 ) (27,28,32). The 

fecal-to-urinary excretion ratio is slightly 

higher (roughly 0.7-0.8) in the first 2 

weeks after inhalation due to ciliary clearance and swallowing of a small portion of 

the lead deposited in the lungs (Fig. 11; 

i 

also see appendix). Urinary plus fecalosses 

during the first 20 days account for about 

Volume 101, Number 7, December 1993 607 

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Research Advances c Leggett 

sumed to be removed from the urinary path 

to the bladder contents with a half-time of 5 

days. The transferate from diffilsible plasma 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 

are reproduced reasonably well by assigning 

0.6% of lead leaving diffusible plasma tO the 

contents of the small intestine. This is in 

addition to the amount assumed to enter 

the small intestine contents via biliary secretion, which accounts for about three-fourths 

of total fecal excretion in this model. The 

transfer rate from 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 indicate that loss of lead in 

sweat can approach or even exceed that in 

urine under some conditions ( 13S13y), 

while other data suggest that sweat is not a 

significant excretion pathway for lead 

(27,14Q). The rate of transfer from plasma 

to sweat used in the present model is a compromise value and is consistent with findings of Rabinowitz and co-workers (S for 

human subjects ingesting a lead isotope 

tracer over a period of months. It is assumed 

that 0.35% of lead leaving diffusible plasma 

is removed from the body in sweat. That is, 

the transfer rate from diffusible plasma to 

sweat is 0.0035 x (2000/day) = 7/day. The 

model predicts that total losses of 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 also contamination 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 

rate from ST1 to excreta of 0.00277/day. 

Fractional transfer from ST1 to excreta was 

based primarily on measurements of excreta 

from human subjects who ingested a lead 

isotope tracer over a period of months (S, 

but data from less controlled 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 extended period. A precise treatment of the 

time-dependent loss of lead in hair, for 

example, from the time of acute intake 

would require 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 blood lead concentration substantially exceeds 25 pg/dl. This 

nonlinear behavior of lead is 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 may have 

a limited capacity for lead (17,145). At low 

levels of exposure, lead in 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, may contain 

one-half tO two-thirds of the lead in 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 

portion of lead found in the main hemoglobin component, 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 level and duration of exposure, and 

some persons may have diminished capacity for synthesizing this protein (3y). 

Another potentially important leadbinding component of RBCs that may 

provide rapidly diminishing binding sites 

at moderate blood lead concentrations is 

the metall oenzyme 6- am i no levul i nate 

dehydratase (AIAD). Apparently, lead ions 

can replace enzyme-activating zinc ions at 

a small number 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 least at 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 

more common AIAD 1-1 isozyme phenotype. 

In the present model it 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 rate from 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 

RBCs or blood at which a reduced rate of 

flow into RBCs should be introduced, or 

even if such a threshold exists. It is asE lllllllll 

as _l w 

CL LLL: | | 

C W | | | |||||| 

1||||||| ___=_ 

|_:_X_ ==T__3_==__ 

Q X= _____|_g_ 

qs __ 

.e |_|__w_ 

; O Xi_ 

0 5 10 15 20 25 30 35 40 46 90 

Hours a"er Intake 

Figure 12. 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 adult human subject (27). 

30% of the administered amount in humans (28), compared with about 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 urinary excretion was estimated to represent about 

0.0035% of the current body burden as 

determined by in vivo mfflcurements (107). 

The present model predicts that daily urinary excretion at 43 years after acute intake 

of lead would be 0.0049% of the current 

body burden. 

Some authors have expressed urinary 

clearance oflead 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 blood volume. In humans exposed only tO environmental lead, urinary dearance of lead is typically 0.02 (range, 0.015-0.03) blood volumes 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 13 and discussed 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 and BPb, insofar as comparisons are possible. In this model, the nonlinear relationship between urinary lead and 

BPb is assumed tO result from the increase 

in diffusible plasma lead as a fraction of BPb 

and not from nonlinear 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 Conditions
Research Ad vances p Kinetic model for lead in humans 

sumed here that such a 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 software packages for solving 

compartmental models do not allow the 

use of nonlinear kinetics. 

Because of the uncertainty regarding the 

magnitude (and existence) of the nonlinear 

threshold and saturation 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 baseline values are given. It is assumed that the deposition fraction in RBCs remains at 0.24 until 

the lead concentration, Y, in RBCs exceeds 

a nonlinear threshold level, T, expressed in 

pg/dl RBC. If Y> T, the deposition fraction, 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 saturation concentration of lead in RBCs. This is an empirically 

derived expression that can be used to 

approximate observed relations between 

lead in blood and that in urine or 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 for compartments other 

than RBCs are increased by the factor (1- 

D)/(1-0.24) = 1.316(1-D). The total transfer rate from diffusible plasma to all destinations is assumed to remain at 2000/day 

under all conditions. 

Chamberlain (18) suggested that nonlinear kinetics 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 set at 60 /dl RBC, which corresponds 

to a blood lead concentration of about 25 

/dl. 

Selection of a saturation concentration, 

S, is complicated by its apparent dependence on the level and duration of exposure 

and potential variation from one 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 and plasma 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, may be better for 

consideration of a high, acute intake by a 

person with a history of low intakes (Fig. 

Results of controlled studies in which 

the blood lead level of human volunteers 

_ 15_ 

o 12i4;_ | l |

O L e ! _ 

ae =<=i __ p3-- 2 2 

@ | I 1 - 1 st l_ *1 1 [ '-1[1 * _ | | 

- *l 13' - t1- 

0 20 40 60 80 

Blood Pb (,ug/dl) 

Figur0 13. Model predictions (solid curves} and 

observations {dashed curves) of the urinary clearance 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 history of 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 scattered and the uncertainties in the amount 

of lead absorbed to blood in each case are 

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) introduces a generic approach for development 

of age-specific parameter values for calciumlike elements [also see Leggett (91)]. 

On the basis of data from 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 fractional transfer from plasma tO bone in children in 

association witb the relatively greaterate 

of addition of calcium tO bone in children 

> - w 

X __X__s E 15-= 

____ __w_ 

L * _____L_ 

_|__ 1_-_l 

o - | 

0 20 40 60 80 100 

Blood Pb {,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 soft tissues and excreta in 

children due to relatively greater competition from immature bone; and 3) an elevated rate of transfer from nonexchangeable bone to diffusible plasma in children 

due to an elevated rate of bone turnover. 

Except where there is evidence tO the contrary, removal half-times from soft tissues, 

bone surfaces, and exchangeable bone volume are assumed to be independent ofage. 

For some calciumlike elements, including 

lead, available data are consistent with the 

assumption that the size of the exchangeable pool of bone is greater in children 

than in adults. Within the context of the 

present model structure or the slightly simpler structure used in ICRP Publication 56 

(22), this means that an atom entering 

bone has a smaller probability ofreaching 

nonexchangeableone 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 and co-workers (13,14) 

conduded from data on baboons exposed 

acutely or chronically to2l0Pb 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, 150-day-old, 

and adult Macaca irus monkeys, skeletal 

tissues of the two younger groups contained a substantiallyarger portion of systemic 2l0Pb than did those of adult monkeys at 4 days after oral dosing (5(J). In a 

similar experiment with rhesus monkeys, 

infants (ages 5-7 months) excreted asubstantially smaller fraction of the absorbed 

amounthan did adults during the first 23 

days after administration (156). 

Another perspective on differences with 

age in the biological behavior of lead is 

provided by autopsy data on human subjects exposed to environmental lead. These 

data can be used to derive reference organ 

Volume 101, Number 7, December 1993 609 

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Table 3. The distribution of lead in humans chronically exposed to a low level of lead throughout life, as 

calculated from postmortem data and as predicted by 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, and these reference distributions 

can serve as constraints on model parameters. Several different adult populations 

have been studied, but reference distributions for children must be based to a large 

extent on data from a single study involving 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 first estimates rather 

than definitive data. 

The derived reference organ distributions 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 be described indetail 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 lead concentrations determined in the relatively detailed investigations by Gross and co-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 toa liver concentration of 1 ppm wet weight. Concentrations reported by Barry (114) were 

used as baseline values for the younger ages. 

Data from these studies were compared 

with findings from a variety of less comprehensive post-mortem studies in an effortO 

determine how well these baseline organ 

contents might represent an arbitrary 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 varied simultaneously within reasonable ranges of uncertainty. It was considered, for example, that 

1) the relative concentrations of lead in different organs vary from one study group to 

another; 2) there may be problems associated with analytical techniques and contamination of samples, particularly for tissues 

with low concentrations of lead; 3) the 

sampling sites may not be representative of 

the whole organ or tissue; and 4) the mass 

of tissue represented bya reported concentration is often not well known (e.g., trabecular bone usually contains more soft tissue 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 for children, the reference distributions were first used to test provisional parameter values for children that were based on 

a set of generic assumptions concerning differences with age in the behavior of calciumlike elements. Some adjustments of the 

provisional parameter values were then 

made to obtain acceptable agreement 

between model predictions and the reference distributions for young children. Itwas 

found that the predicted age-specific distributions varied little with the exposure scenario, provided the rate of uptake of lead to 

blood was not radically altered over a period 

of a few months. Thus, predictions were 

based on a simple scenario of constant 

uptake (20 pg/day) to blood throughout 

life. In this model, the lead content of the 

various compartments at birth are derived 

from the assumed content in the mother's 

blood. The concentrationf lead in blood 

at birth is assumed to be 0.85 times that of 

the mother's blood, based on a variety of 

studies (167). The relative contents of bone, 

blood, liver, kidneys, brain, and other soft 

tissues at birth are assumed to be 0.32, 0.07, 

0.055, 0.01, 0.045, and 0.5, respectively, 

based mainly on data of Barry (114); for 

multiple-compartment organs, the contents 

at birth are assumed to reside in the longestterm compartment. For the exposure scenario considered here, the concentrationf 

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 provisionalge-specific parameter 

values were based on the followingeneric 

assumptions (1-5 below), which were 

applied earlier tO the alkaline earth elements (22,91). 

Generic assumption 1. Fractional deposition on bone surfaces is proportional to

the rate of addition of calcium due to 

modeling and remodeling of the given 

bone type (trabecular or cortical). The estimated average calcium addition rate for 

adults (0.25 g/day) and the deposition 

fraction for bone in the typical adult serve 

as the points of reference. The model for 

the rate of addition of calcium to the skeleton 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. The model for the rate of 

turnover of cortical and trabecular bone in 

children is described elsewhere (21,97). 

Generic assumption 3.At all ages, 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 few years of life. As it turns 

out, model predictions are fairly insensitive 

to the division between cortical and trabecular bone in children because, as indicated 

by data for the alkaline earth elements and 

depicted in this model, there is little distinction between trabecular and cortical 

bone in children with regard to the kinetics 

of calciumlike elements. The model depicts 

trabecularnd 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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Research Advances ) Kinetic model for lead in hLlmans 

generic assumption 1, the estimated trabecular to cortical deposition ratio of a calciumlike element increases from 0.25 in 

infants (since there is assumed to be onefourth as much trabeculars cortical bone 

and the growth and turnover rates are 

assumed tO be the same for the two bone 

types in infants) to 0.34 at age 10 years, for 

example, and to 1.25 in mature adults. 

Bone originally laid down as trabecular 

bone but converted to compact bone during growth is assumed tO have been cortical 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 the distribution 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 soft tissues and 

excreta of children is described in terms of 

the remaining 50% of outflow from diffusible plasma. As an example, the deposition fraction assigned to all bone surfaces 

combined is 0.08 for mature adults and, as 

derived from generic assumption 1, 0.24 

for infants. 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 

with the 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 are independent of age. As described later, it seems 

appropriate to relax this assumption for the 

case of lead in the liver and kidneys. Also, 

limited information suggests that the rate 

of removal of alkaline earth elements from 

exchangeable bone may be greater in children than in adults, but the present assumption seems reasonable until age-specific rates can be better supported and 

quantified. Note that this assumption 

applies to total outflow from bone surfaces 

and exchangeable bone volume and does 

not address the destination ofoutflow. 

A sixth assumption regarding the relative exchangeability ofbone deposits in 

children and adults is applied in ICRP 

Publication 56 (22^) on an element-by-element basis. There is 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 earth elements because it appears to be less pronounced for calcium than for strontium 

(91). An assumption ofelevated exchangeability of bone deposits in children leads to 

improved agreement between model predictions and autopsy data on persons 

exposed to environmental 90Sr and thus is 

applied by ICRP (22) to strontium. This 

assumption could not be tested for barium 

and radium and is not applied in the ICRP 

document to these elements. The assumption is implemented for strontium by 

assigningreater fractional transfer from 

bone surfaces to diffusible plasma in children than in adults. It could be implemented in other ways,- such as by assigning 

a greater fractional return from exchangeable bone volume to bone surfaces in children, but the available data on strontium 

seem consistent with the requirement that 

the elevated exchange of bone strontium in 

children be manifested fairly rapidly. 

There is no direct evidence of decreasing exchangeability of lead with increasing 

bone age. The situation for lead is otherwise similar to that for strontium, however, 

in that an assumption of elevated exchangeability of bone deposits in children 

helps reduce discrepancies between predictions of a provisional model based on 

assumptions 1-5 and autopsy data for 

environmentally exposed children. Therefore, the following assumption is made for 

lead. 

Assumption 6. There is greater fractional transfer from bone surfaces to diffusible 

plasma in children than in adults. By analogy with strontium, it is assumed that fractional return from bone surfaces to plasma 

is 1.25 times higher at ages 0-15 years 

than in adults. For lead, this means 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 bone surfaces is assumed to be 1/day, as in adults 

(see generic assumption 5), the transfer 

rate from (trabecular ocortical) bone surfaces to diffusible plasma in children is 

0.65 x (1/day) = 0.65/day, and the transfer 

rate from bone surfaces to exchangeable 

bone volume is 0.35/day. 

The addition of assumption 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 and kidneys do not appear to be important repositories of lead in young children, but if the 

parameter values for adults are applied tO 

these organs during childhood, the model 

predicts substantial buildup in the first few 

years of life, due mainly tO accumulation 

in the long-term compartments assumed to 

exist in each organ. Thus, it seems reasonable to reduce the removal half-time for 

these compartments in young children. 

Assumption 7. The removal half-time 

from the long-term compartments of liver 

and kidneys to diffusible plasma is 100 

days for ages 0-5 years. The removal halftime for ages 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 the transfer 

rates given in the table. 

Although some discrepancies remain 

between model predictions and reference 

distributions after application ofthe seven 

assumptions indicated above, further complications of the model based on these reference distributions for children do not 

appear to be justified for purposes of radiation protection. For example, assumptions 

1-7 yield higher fractional content in 

blood and lower fractional content in other 

soft tissues than indicated by the reference 

distributions for children. Estimates of 

dose from internally deposited radioisotopes of lead are not altered much, however, by forcing the model to fit the reference 

values for other soft tissues and blood; this 

is because the predicted and reference distributions agree reasonably well with 

regard to the sum of the 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 up other soft 

tissues. 

While the ability to predict the level of 

lead in blood in chronically exposed children may not be critical for radiation protection 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 into the model 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 be smaller uptake of 

lead by RBCs and/or faster removal from 

RBCs in young animals than in mature 

animals. Also, model predictions for children can be brought into line better 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 choosing between these two 

approaches, excepthat within the present 

scheme it is simpler to assign a shorter 

removal half-time. 

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611 

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Reseal-c/^ Acivaces 0 Lepett 

Summary and Conclusions 

Several differentypes of information contribute to our understanding ofthe behavior 

of lead in the human body. These include 

results of lead tracer studies on healthy adult 

human volunteers; measurements oflead in 

autopsy samples from environmentally 

exposed humans of all ages; results of lead 

balance studies on adult humans; bioassay 

data and autopsy measurements on persons 

occupationally exposed tO lead; data from 

controlled studies of the behavior of radiolead in laboratory animals at different 

stages of life; and data on the age-specific 

kinetics of the chemically and, in many 

respects, physiologically similar alkaline 

earth elements in humans and laboratory 

animals. 

In this paper an attempt has been 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 for consideration of the 

age-specific biokinetics of a class of calciumlike radionudides. The model structure represents a compromise between biological 

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 nonlinearelation between plasma lead and red blood cell lead is modeled 

for concentrations above that level. 

The model appears to be a fairly accurate predictor for adult humans exposed to 

relatively low levels of lead. It is proposed 

only as 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 model is 

intended to allow researchers tomodify specific parameter values or model components 

to addresspecial problems in lead toxicology 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 the model. 

Appendix 

Respio and 4iZ 

Tract Models l;or T esd 

Rzspiratoty TractModel 

Fractional deposition of inhaled lead in the 

lungs varies with the size of the inhaled 

material, the breathing rate, and other factors. A value of about 0.354.40 may be 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 is shorter in young children than 

in adults. The following removal half-times 

from RBCs to diffusible plasmare chosen 

for reasonable consistency with the reference 

distributions: ages 0-1 years, 1.5 days; ages 5 

years, 2.5 days; ages 2 10 years, 5days. 

The derived reference distributions indicate that the fractional content of other soft 

tissues is considerably greater in young children than in adults. The relatively high content estimated for this group of tissues at 

young ages can be traced to the high portion of the body weight represented byskin 

and fat and the high reported concentrations of lead in fat in young children compared with adults. The high reported concentration oflead in fat in children could be 

partly an artifact of the autopsy data, given 

the considerable technical problems in 

obtaining representative samples of fat and 

accurately determining the low 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 for compartment 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 

lead after the other compartments have 

been addressed. 

Assumption 9. The deposition fraction 

in the intermediate-turnover compartment, 

ST1, is two times higher at ages 0-15 years 

than in adults. The higher deposition in 

ST1 at these ages is 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 soft tissues. Although 

autopsy results indicate that the concentration of lead in brain may be lower in children than in adults, the brain 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 of total body mass) at 

the younger ages. This is supported by 

comparative data on mature and immature 

baboons administered radiolead (18). In 

this model, the relatively 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. The deposition fraction 

for brain is assumed to dedine linearly with 

age to 5 years, when the adult value is 

reached. The higher 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 biological half-time on the order of 

0.2-0.6 day, if clearance is expressed in 

terms of one or tWO components (27,31, 

32,42,44,45,165,166). Similarly, abiological half-time of about 0.5 day has been 

found for dogs (167). A more detailed 

description was given by Chamberlain and 

co-workers (27), who found that for deg0o3sited 203PbO, 2°3Pb(NO3)2, or "dean" 

Pb-labeled exhaust aerosols, approximately 22% 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 depends on 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) and Wells et al. 

(3X indicate that about 95% of deposited 

lead was absorbed directly tO blood. When 

inhaled as a vapor, as much as 3540% of 

deposited lead might be removed to the 

stomach, and the rest is absorbed directly 

to blood (31). 

Based on 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 lung deposition 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 blood and 

5% moving to the stomach via ciliary 

dearance. Greater ciliary clearance may be 

expected in industrial exposures, where 

aerosol particles are often larger (18), or 

with lead inhaled as a vapor (31). It is 

assumed that the behavior of lead deposited in the lungs is independent of age. 

Gasjrogn EractModel 

For persons 2 18 years old, movement of 

lead through the gastrointestinal tract is 

assumed to follow the gastrointestinal tract 

model of 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 only in segment SI. 

612 Environmental Health Perspectives 

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Research Advances @ Kinetic model for lead in humans 

13. Mallon RP. A metabolic model of lead kinetics 

based upon measuled organ burdens during 

chronic exposure experiments with infant and 

juvenile baboons (dissertation). New York New 

York University, 1983. 

14. Kneip TJ, Mallon RP, Harley NH. Biokinetic 

modelling for mammalian lead metabolism. 

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 variable absorption in humans without excessive lead exposures. Environ Res 36:459-472(1985). 

17. Marcus AH. Multicompartment kinetic models 

for lead. III. Lead in blood plasmand erythrocytes. Environ Res 36:473-489(1985). 

18. Chamberlain AC. Prediction of response of 

blood lead to airborne and dietary 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 the prediction of lead body burdens. 

Environ Res 48:117-127(1989). 

20. O'Flaherty EJ. Physiologically based models for 

bone-seeking elements. II. Kinetics of lead disposition 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 the retention, translocation, and excretion of systemic plutonium. 

Health Phys 49:1115-1137(1985). 

25. Leggett RW, Eckerman KF, Wllliams LR An 

elementary method for implementing complex 

biokinetic models. Health Phys 64:260- 

278(1993). 

26. Vander AJ, Taylor DL, Kalitis K, Mouw DR, 

Victery W. Renal handling of lead in 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 of lead by 

human skeleton and comparative metabolism 

of lead 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 variabilityO 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, Newton D, 

Stott ANB. Uptake of radioactive lead following 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: Inhaled particles IV, Proceedings of a symposium of the 

Transfer from one segmento another is 

assumed to follow first-order kinetics. In 

adults, transfer rates out of segments S, SI, 

ULI, and LLI are 24, 6, 1.85, and 1/day, 

respectively. For children age 0-12 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 ofthe 12-year and 

18-year values. Lead transferred from the 

liver or from plasma into the contents of 

the gastrointestinal tract is assigned to segment SI and is assumed to be reabsorbed 

to plasmat the same rate as ingested lead. 

Absorption of lead from the gastrointestinal tract has been studied extensively 

and dependstrongly on a variety of factors, induding the level of calcium, phosphorus, zinc, iron, fat, protein, and vitamin D present in the intestines; the body's 

iron or zinc status; the amount of lead 

administered; the physical and chemical 

form administered; and the time 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, 

0.08-0.30 for intake with liquid between 

meals (27,181), and 0.3-0.7 for ingestion 

with liquids 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 lead indicates that an estimate of 0.15 or greater 

might be more appropriate (27,128). 

Balance studiesuggest that infants and 

children may absorb 40% or more of 

ingested lead (185-188), but results of 

these studies are highly variable and inconclusive. Data on 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. For example, the value for age 20 years is (0.5 x 

0.3)+(0.5 x 0.15) = 0.225. 

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