-------
e
o
H
U
-> r
r
r
I
H
en
Cb
O
a
Ed
ao
CM
O er> tN m
r* O O
r-«
O
O O O co
o o sr oo
O O r- r^
po r- o>
00
r- o
l I
l l
ca
!x
en
a
3
31
JJ
ca
>*
ca
o
31
CO
3)
U
ca
>*
CO
T3
01
^j
U
a.
01
'_
S
^
.^
X
-3~
O
M
M^
o
31
U
a.
co
3
<
w
o
as
3
a
M
27
-------
a mechanism of lead exposure. The list of substances commonly
mouthed or ingested by children displaying these behaviors has been
shown to include paper (newspaper, wallpaper, toilet tissue, facial
tissue, cardboard), dirt (soil, dust, clay, sand, ashes), paint and
plaster, tobacco, and toiletries and cosmetics (Barltrop, 1966;
Millican et al., 1962). Some of these are known to contain lead.
Concentrations of lead that have been measured in these substances
are reported in the following sections.
2.4.1 Soil/Dust*
Anthropogenic sources are responsible for the major portion of
lead found in soil and dust. Natural occurrence of lead in the
earth's crust accounts for an average of 15 ng/g (Durum et al.,
1971). Mean rural soil and dust lead levels of 60 and 275 |j.g/g have
been reported (Rolfe and Haney, 1975; Bethea and Bethea, 1975).
However, lead levels in soil and dust in metropolitan areas are said
to be as high as 20,000 ug/g (Jenkins, 1976). The mean interior
house dust-lead level for an urban area was reported as 11,000 M-g/g
(Lepow et al., 1974). Metropolitan soil-lead levels as high as 3357
p.g/g have been reported (NAS, 1972).
The combustion of leaded gasoline is a major contributor to the
high lead levels in urban soil and dust (NAS, 1972). Lead levels of
about 75 to 730 |j.g/g have been found in soil adjacent to low and
high traffic volume streets, respectively (Johnson et al., 1978).
Additional data from this study suggest a correlation between urban
air-lead concentrations and lead levels in hand-wipe samples from
children. Since urban atmospheric lead concentrations are related to
traffic volume (Section 2.1), these indvcate a relationship between
Soil and dust will be treated as a single entity in later
calculations and therefore will commonly be designatd "soil/dust".
28
-------
gasoline combustion and urban soil/dust-lead. Soil lead concen-
trations diminish with distance from roadways, but increase
significantly near dwellings (Rolfe and Haney, 1975). Increased
levels of soil lead near dwellings have been reportedly due to runoff
of lead particulates from vehicular aerosol deposition (Rolfe and
Haney, 1975), and from the weathering of paint on outer surfaces of
dwellings (Ter Haar and Aronow, 1974). High interior dust lead
levels (11,000 H-g/g) on unpainted surfaces were reported to be a
result of outdoor vehicular aerosol contamination (Lepow et al.,
1974). Soil concentrations near U.S. highways displayed decreased
concentrations with increased distance from roadways, as well as with
increased soil depth. Lead concentration reduction of 65 to 75
percent occurred within a distance of 24 meters from the road (from
32 to 8 M-g/g) where traffic densities ranged from 7500 to 48,000 cars
per day (Lagerwerff and Specht, 1970).
Industrial point sources (e.g., smelters and battery plants) are
a major local source of soil/dust-lead contamination. Air and soil
levels were shown to decrease with increased distance from a smelter
site in El Paso, Texas. Soil lead concentrations within 1 mile of
the smelter averaged 36,853 ng/g, but declined to 2726 ng/g at 1.1 to
2.0 miles and to 2151 H-g/g at distances over 4 miles (Landrigan et
al., 1975). A smelter study in Silver Valley, Idaho, displayed
significantly increased air and soil-lead levels at distances of up
to 16 miles from the source (Idaho Department of Health and Welfare,
1977). It is apparent that industrial point sources of lead
emissions can affect soil levels for much greater distances than
those induced by low level vehicle emissions.
Lead particles are emitted from vehicles initially as halogen-
ated compounds, of which lead chlorobromide is the most abundant.
These lead particulates lose the halogens, shift toward small parti-
cle sizes, and increase their water solubility during airborne trans-
port via chemical reactions which are enhanced by light and S02«
Lead oxide, lead carbonate, and lead sulfate are the major chemical
29
-------
forms prevalent after deposition of lead particles (Ter Haar and
Bayard, 1971; EPA, 1977). These results are in agreement with Olson
and Skogerboe (1975), who found the major lead contaminant of soil
and dust to be lead sulfate.
2.4.2 Paint
Ingestion of paint by children suffering from pica has been
associated with numerous cases of childhood lead poisoning. Epide-
miological evidence indicates an association between elevated blood-
lead levels a'nd children with pica for paint (HAS, 1972).
, Pica for paint is of major concern. Extremely high lead
concentrations are found in some older paint coatings and are still
available as peeling and flaking paint (indoor and outdoor) on older
dwellings. A survey of over 2000 dwellings in Pittsburgh revealed
that at least 20 percent of the residences built after 1960 had at
least one surface with an excess of 1.5 [jig/cm^ lead (Shier and
Hall, 1977). Smaller surveys in El Paso, Texas and Silver Valley,
Idaho, found indoor paint-lead concentrations of >1 percent by weight
(10,000 |ag/g) (Landrigan et al., 1975; Idaho Department of Health and
Welfare, 1977).
Market surveys in 1971 showed 8 of 76 paints tested contained
2.6 to 10.8 percent lead. The Consumer Product Safety Commission
found that only 2 percent of interior paints tested had lead levels
exceeding 1 percent (HAS, 1976). The same survey found that 70.8
percent of oil-based paints and 96.1 percent of water-based paints
contained less than 0.06 percent lead (the current paint standard).
Regulation of the use of lead in house paints did not exist
until 1955, when a 1 percent voluntary standard was adopted. A
federal standard of 1 percent was imposed in the early 1970s, lowered
to 0.5 percent in 1976, and further lowered to 0.06 percent (600
H-g/g) in 1977. It is apparent that paint with lead levels in excess
of 1 percent (by weight) is still readily accessible to children who
live in older dwellings (NAS, 1976).
30
-------
2.4.3 Newsprint
Newsprint can be comprised of up to 1 percent lead (by weight)
(Hankin et al., 1974). Colored newsprint contains the greatest
amounts of lead. Handling newsprint may result in appreciable dermal
exposure; and, coupled with immature dietary habits (e.g., the
licking and sucking of fingers), newsprint may represent a source of
ingested lead as well. Ingestion of newspaper is common among
children with pica. Indirect newsprint-related exposure can result
from elevated air lead levels in homes where newspapers and magazines
are used as fireplace fuel (Perkins and Oski, 1976).
2.5 Other Lead Sources
2.5.1 Lead-Glazed Utensils
A number of persons have been poisoned by lead that has leached
from glazed kitchen utensils. Studies have indicated that the amount
of lead leaching into a beverage from the glaze of a ceramic vessel
is a function of the temperature at which the glaze was fired, how
long the drink has remained in the vessel, the pH of the drink, and
the number of times the vessel had been used previously. In one
study, lead concentrations in a cola (pH 2.7) stored in a glazed mug
increased by 2800 (JLg/1 after two minutes and by 6600 ng/1 after two
hours of containment (Harris and Elsea, 1967).
2.5.2 Occupational Exposures
Workers whose occupations entail chronic exposure to high lead
levels (e.g., garage mechanics, police, smelter workers) have been
shown to have higher mean blood-lead levels than other workers (EPA,
1972a; Johnson et al., 1975b). In some studies, more than 50 percent
of such high risk populations have been shown to have blood-lead
levels MO H-g/dl, far higher than the 1 to 5 percent representative
of the average adult population (EPA, 1972a).
31
-------
Prudent industrial hygiene practices can minimize excessive
occupational lead exposure. Since this discussion is centered around
the possible environmental lead exposure sources, as opposed to spe-
cific occupational categories, occupational lead exposures will not
be discussed further.
2.5.3 Smoking
Tobacco smoke is an additional source of respiratory lead expo-
sure. Reports indicate that inhaled cigarette smoke may provide from
20 to 66 |j.g of lead per pack (Schroeder and Balassa, 1961; Patterson,
1965). Contrasting information suggests that the high blood-lead
levels in some individuals who smoke can be attributed to the contam-
ination of fingers and cigarettes from nontobacco sources and the
deleterious effects of smoking upon lung clearance mechanisms (Tola
and Nordman, 1977).
32
-------
3.0 ABSORPTION, RETENTION AND ELIMINATION OF LEAD IN HUMANS
Lead is absorbed into the body via inhalation, ingestion, or
dermal contact, enters the bloodstream, and is transported throughout
the body. The concentration of lead in the body is a function of the
level and duration of exposure, the rate of absorption, and the rate
of elimination.
Once lead has entered the bloodstream, it can be transported to
most sites within the body. Lead is removed from the blood by excre-
tory mechanisms (e.g., kidney) or by gradual accumulation at various
storage sites (e.g., soft tissue, bone). Toxic symptoms result when
the lead concentration in a particular body compartment is suffi-
cient to cause damage. When assessing the toxicological implications
of environmental lead exposure, it is important to consider the expo-
sure route because the kinetics of absorption vary between routes.
3.1 Absorption Characteristics
Environmental lead compounds can be absorbed into the blood-
stream from the lung after inhalation, from the gastrointestinal
tract after ingestion, or to a limited extent, from direct dermal
contact. The absorption kinetics for each of these pathways are
%
dependent upon a number of factors, including the physical and chem-
ical nature of the lead compounds at the time of exposure and the
presence of other modifying agents. Once inorganic lead is absorbed
into the bloodstream (where it is mainly bound to erythrocytes [Butt
et al., 1964]), it is readily transported to other locations in the
body and does not normally retain any characteristics associated with
its exposure or absorption route. Although inhalation and ingestion
of lead-containing compounds are the predominant routes of intake,
dermal absorption may be significant under certain circumstances
33
-------
(e.g., occupational lead alkyl exposure). The three absorption
routes are discussed in detail in the following sections.
3.1.1 Pulmonary Absorption
To be absorbed into the bloodstream, inhaled lead material must
be retained in the lower regions of the lung (pulmonary region) long
enough to be solubilized. Lead vapors freely penetrate deeply into
the lung, but the penetrability of lead-containing aerosols is
dependent on several variables, the predominant one being particle
size. Since most atmospheric lead compounds exist as a component of
particulate matter, the uptake of lead vapors can be ignored (Smith,
1971). ,
Physical retention of particulate matter in the lung is a func-
tion of particle size and breathing kinetics, while the chemical
properties of the particle determine its solubility in body fluids,
and hence its ultimate absorption. If particles are deposited in the
upper regions of the respiratory tract (i.e., nasopharyngeal and
tracheobronchial regions), they can be removed by the ciliated
epithelium (mucocilary escalator) relatively quickly and expectorated
or swallowed. Particles deposited in the pulmonary (i.e., alveolar)
region, which is devoid of cilia, can be absorbed into the blood-
stream or phagocytized by alveolar macrophages and removed via the
lymphatic system (Casarett and Doull, 1975). If a particle is larger
than about 10 (j. in diameter, it is deposited by inertial impaction in
the nasopharyngeal region and removed. Particles between 1 and 5 JJL
often settle out in the tracheobronchial region and are similarly
removed. ,Various lung deposition models suggest that the greatest
retention in the pulmonary region of the-lung occurs for particles
with an aerodynamic diameter in the 0.1 to 1 ^ range (Task Group on
Lung Dynamics, 1966; Nozaki, 1966).
As indicated in Section 2.1, the particle size distribution of
ambient lead aerosols tends to be within the respirable range.
34
-------
However, one should not assume that all of the respirable lead mate-
rial inhaled is subsequently absorbed into the bloodstream because
the chemical form of the particle can affect the rate of absorption
(Smith, 1971; Kehoe, 1969). The major species of atmospheric lead
particles include various lead halide mixtures and lead oxide,
phosphate, or sulfate (NAS, 1972). Since some of these compounds
tend to be only slightly soluble in biological fluids, it is
difficult to predict the degree to which they are actually absorbed
within the lung.
Empirical evidence, from lead balance and lead tracer studies,
indicates that from about 20 to 50 percent of inhaled lead particles
(i.e., those particles representative of urban atmospheres) are
absorbed into the bloodstream (see Table 3-1). In some cases, both
retention in the lung and absorption into the bloodstream were
monitored; while in other cases, only particle retention was deter-
mined with subsequent absorption assumed. Based on these studies, 40
percent is a reasonable value for lead absorption into the blood-
stream from ambient lead aerosols in an adult.
The absorption of lead from ambient aerosols by children is not
as well defined. Several problems, including differences in respira-
tory physiology, metabolism, and body compartment size, make absorp-
tion projections in children, based on data from adult, tenuous
(Knelson, 1974). In addition, ambient monitoring data may not
necessarily reflect the actual atmospheric dose to which a child (or
an adult) is exposed, since there is often an increase in the
particulate concentration gradient as one approaches ground level
(see Section 2.1). Without definitive clinical studies of atmo-
spheric lead retention and absorption in children, one must make
projections based on adult data and modify them by known differ*-
in ventilatory exchange. As a result, one must assume similr
absorption and retention characteristics in adults and ch*
varying exposures.
35
-------
o
§
rH
CO JO
4J
00 01
3 Si
a u
3 o
01 4-1
B
b IH
O
W 13
§01
J3
b
B 9
iH 01
J
co a
01
rH CO
o a
H 3
4J
b Si
a u
Q. IH
Si
o 3
a
01 u
rH 0
UH 4J
0 S
u
B CJ
O b
IH 01
4J Q.
iH
CO OS
o sr
Q.
01
"O 4J
c
oo oi
B U
3 b
rH 01
Q.
rH
a o
IH -a-
u
iH CO
B a
M 3
oo
B
H
rH
5
C
rt
00
§
H
4J
a
rH
3
O.
Q
O.
B
a
-a
b
3
UH
O
9]
01
*r4
T>
3
4J
CO
01
CJ
a
b
4J .
CO
J3 rH
0. O
O CO
rH O
CN b
01
B a
0
b ja
UH CU
T3 -u
01 B
CJ 01
3 *
o ja
CH §
.
CO
01
rl
a
3
4J
01
>.
b
a
4-1
01
IH
13
.Q
0,
O
rH
CM
>,
.a
a
01
B
H
UH
01
o
01
<
00
s
t>
ooo)
§B CO
rt 01
rH 01 iH
« -a
B a 3
-rt b u
0]
01 U
-H a b
cj js oi
iH 4J O
u a
b«H b
a o 4J
u-i C Q.
0 01 0
U u
E kl 0
o oi n
H 0.1H
t-l O
B O iH
oi m TJ
u a
01 rS kl
b-H
e S
..00
91 b
01 01 UH
rH i-H
o IH a
H .B u
u 3 a
b TJ
a -
a. 4J ..
B -a
u 01 O
01 u o
3 b rH
a oi ja
.B a
x o
0) O> 4J
in B
01 -rt
> 0
IH U 13
4J (I)
o in ja
a » b
o o
4J CO CO
3 a J3
< 3 a
percent
mospheric
ii
a a
2 a
a
J3
CO b
rf3
3 u
rH B
01
B IH
rt -a
B§
O
iH
4J T)
s 3
ot e
4J iH
oi a
b 4J
41
01 ki
4J
a n
rH Ot
3 rH
CJ U
n tH
4J U
b ki
a a
o. a.
U 01
a 01
01 O
u si
b 4J .
01 CO
CUUH 01
O rH
0 U
.
4J J3 b
oj a
CO O B
4J O
a 13 rH
rt B 3
b 3 a
4j a
§UH UH
o
a w
c o oi
rt B 4-»
a
BBS
a o
-------
Inhaled lead-containing particles larger than one or two microns
in diameter are usually collected in the nasopharyngeal or tracheo-
bronchial regions of the respiratory tract, removed via ciliary
action and expectorated or swallowed. That fraction which is swal-
lowed may be absorbed in the gastrointestinal tract, but its contri-
bution relative to other sources of ingested lead is unknown. Some
studies utilizing artificially generated aerosols have indicated that
up to 40 percent of inhaled lead particles (mass median diameter of
2.9 n) deposited in the airways are transferred to the gastrointes-
tinal tract (Kehoe, 1961). However, gastrointestinal absorption of
inhaled lead from ambient urban atmospheres is expected to be insig-
nificant given the particle-size distribution of such aerosols.
3.1.2 Gastrointestinal Absorption
The absorption of lead-containing compounds in the gastrointes-
tinal (Gl) tract is dependent upon the physical/chemical form of the
material ingested, and can be affected by other factors including the
composition of the diet and the age and physiological status of the
individual. Absorption of lead from the GI tract appears to be a
passive diffusion process, but may be regulated to some extent by the
mechanisms controlling calcium and phosphorous absorption (Casarett
and Doull, 1975; Gruden and Stantic, 1975).
In the average adult, approximately 10 percent of ingested lead
is actually absorbed into the bloodstream. As indicated in Table
3-2, however, empirical evidence indicates large variations in the GI
absorption of lead in humans. In some studies, the lead absorption
in particular individuals approached 70 percent of the total amount
ingested, but in most instances, a value of approximately 10 percent
was reported. Such variations may be a result of individual GI tract
differences, discrepancies between experimental protocols (e.g.,
balance versus tracer studies), chemical dissimilarities between the
form of lead administered, or analytical error (Blake, 1976;
Wetherill et al., 1974).
37
-------
>rmal individuals;
= «
i/l x
<0
c -o
H
CO
a M
91
f4 O
13 u
3
U CM
a FH
91 U
U O
a "-i
a
Empirically d
of individual
u
o
1
IM
X
A
U
i
u
91
.a
2
*
w
41
^4
«
fH
i
§
5
^
91
4J
a
91
9
H
u
e
Based on amou
water.
o
a
9)
rH
X
h
(9
All
01
^4
O
1*4
O
a
91
U
VI
I
u
91
^
a
3
U
a
i>
o
o
<*4
U
o
»»
S
A
00
a
*4
U
a
<9
«4
a
4J
91
t4
O
u
a
V
u
91
»w
>u
o.
o
f*4 4J
tracer (
r exhaus
O 0
Based ou radl
ingesting mot
n lead tracer studies
0 percent during fasting
01-
13 o
91 U
a
Jo.
a
TJ ^
O 91
O 00
4-l
o
S-
Vi S
0 01
fH U
H U
X 91
u a.
xao
J=fH
U
fH a
a 19
«»
T3
oo ta
91
OOrH
Involvin
bsorbed
19
Balance study
retention of
s
01
w
o
fH
«H
"3
a
H
C
a
H
4j
a.
u
0
91
J
.ntestinal a
gastroj
01
RepresentatiM
I. S
Re
omp
a a
S J
00
Irf
9)
0
O
w
a.
^4
H
1
hroed
-H
4
Wethe
d
m
r«»
CJ\
V
5
Chambe
bl
975
ST u
>W 91
52 S
U U (N
-------
In children, the GI absorption of lead can vary, due in part to
the source of the lead ingested and its physical/chemical charac-
teristics. Based on data shown in Table 3-2, it is conservatively
assumed that approximately 50 percent of the lead in food and water
is absorbed. This fivefold difference in the GI absorption rates of
children and adults has been related to the differences in the
metabolic behavior of lead at different ages (Kostial et al., 1971;
Momcilovic and Kostial, 1974). Experiments involving weanling rats
fed lead chloride confirm the finding of substantially increased GI
absorption in the young (Kostial et al., 1971; Forbes and Reina,
1972).
Children with pica may ingest a substantial amount of lead-con-
taining substances. Paint is a source of lead for some children with
pica. The lead in paint is believed to be absorbed at a different
rate than lead in food and water. Animal studies have shown that
lead in paint is not absorbed as well as the simple inorganic salts
present in other sources. The data indicate that the forms of lead
contained in paint are absorbed only one-fourth to one-half as well
as the lead salts. A 17-percent rate of absorption for lead in paint
has been estimated (NAS, 1976). It must be emphasized that due to
high variability of several factors, this absorption rate is only
suitable for use on a group basis.
No definitive studies have been conducted on the absorption rate
for ingested lead from soil/dust. It appears that this is a major
source of lead and that many children ingest substantial amounts of
soil/dust from normal hand-to-mouth activity. It is generally
assumed that within the gastrointestinal tract lead is more easily
separated from the physically absorbed soil fraction than from the
chemically bound fraction in paint. Analysis of lead in soil/ dust
and paint from an area impacted by a smelter showed that 20 to 60
39
-------
percent lead in surface soil was extractable in 0.1N HCl (rep-
resentative of the human stomach) compared with less than 10 percent
extracted from paint samples (Roberts et al., 1974). A rate of 30
percent has therefore been selected as a representative figure for
the absorption of lead from soil/dust, reflecting an absorption rate
intermediate between dietary lead and paint lead uptake.
A number of factors affect the degree of lead absorption in the
GI tract. Variations in the chemical form of the ingested lead mate-
rial can alter the absorption rate. Lead tracer studies in fasting
adults have indicated that lead nitrate is absorbed at about three
times the rate of lead sulfide (i.e., 41 and 14 percent, respective-
ly) (Wetherill et al., 1974). Nutritional factors may also affect GI
absorption of lead (Barltrop and Khoo, 1975a, b; 1976); short-term
studies using 2°3pb tracer in rats detected a twentyfold increase
in absorption for those animals fed diets deficient in minerals and a
sevenfold increase for those on high-fat diets (Barltrop and Khoo,
1975a). There is also a pronounced tendency toward greater absorp-
tion when lead is ingested without food (Wetherill et al., 1974;
Garber and Wei, 1974; Quarterman et al., 1976). Although it has been
suggested that lead in drinking water is absorbed in the GI .tract at
twice the rate of lead in food (Patterson, 1965), definitive labora-
tory evidence of such a preferential absorption is currently unavail-
able. In the absence of such data, equivalent GI absorption rates
for lead in food and water on the order of 10 percent in adults, and
about 50 percent in children, have been assumed.
3.1.3 Dermal Absorption
In order to be absorbed through the skin, lead must either pass
through the epidermal cell layer, the sweat or sebaceous glands, or
the hair follicles. Uptake via the sweat glands or hair follicles is
not significant. The epidermal layers are not highly permeable and
restrict the absorption of most inorganic lead compounds. However,
40
-------
since the skin is a lipid barrier, organic lead compounds are able to
pass through and be absorbed.
Clinical studies have indicated that organic lead compounds
(e.g., lead naphthenate, lead acetate) can cross the epidermal layers
to varying degrees and result in elevated blood-lead levels (Rastogi
and Clausen, 1976). Alkyl lead compounds are also readily absorbed
through the skin (Gething, 1975), and have caused episodes of acute
lead poisoning.
The dermal absorption of lead compounds, however, does not
appear to be a significant exposure route for the general population.
Although organic lead compounds are quite capable of passing the skin
barrier, the major source of exposure is occupational (e.g., garage
mechanics, gasoline distributors). As mentioned in Section 2.1,
alkyl lead concentrations in urban atmospheres are probably consider-
ably less than 10 percent of the inorganic lead values (NAS, 1972).
3.2 Retention Characteristics
Postmortem analyses of tissue samples from persons with no occu-
pational exposure to lead have demonstrated the presence of the metal
in virtually every organ of the human body (Barry, 1975; Gross et
al., 1975).
The body burden of lead is not distributed uniformly; lead has
an extremely high affinity for calcareous tissue (Table 3-3). Over
90 percent of the lead stored in the adult body is located in the
skeleton. In one study (Barry, 1975), the average body burden of
lead in 50 male adults was 164.8 mg, of which 155.5 mg (94.4 percent)
was located in bone. Children were found to have both a substan-
tially lower body burden of lead and a lower percentage of this body
burden contained in their bones (Table 3-3). The average body burden
of lead in 23 children (mean body weight 23 kg) was 12.3 mg, 72.5
percent of which (8.9 mg) was located in bone. However, concentra-
tions of lead in the majority of soft tissues of children were either
41
-------
TABLE 3-3
LEAD CONCENTRATIONS IN VARIOUS TISSUES
OF CHILDREN AND MALE ADULTS
(ppm Wet Weight)
Tissue Male Adults Children (2-9 Years)
Tibia
Rib
Liver
Kidney
Cortex
Medulla
Prostate
Spleen
Lung
Skin
Thyroid
Brain Cortex
Stomach
Heart
23.4
8.85
1.03
0.78
0.50
0.27
0.23
0.22
0.19
0.19
0.10
0.09
0.07
3.70
3.01
0.87
0.70
0.49
0.48
0.13
0.19
0.63
0.28
0.09
0.11
0.09
SOURCE: Adapted from Barry, 1975
42
-------
the same as or higher than those in the corresponding tissues of
adults (Table 3-3).
Lead concentrations in the majority of soft tissues apparently
reach an equilibrium level during the second decade of life and
remain at this level indefinitely (Barry, 1975). Concentrations in
the bones, aorta, liver, lungs, kidneys, pancreas and spleen continue
to increase with age (Schroeder and Tipton, 1968). While some
studies have reported that this increase continues indefinitely
(Barry, 1975; Barry and Mossman, 1970), others have noted a decrease
in the lead burdens of many soft tissues beginning in about the
eighth decade (Gross et al., 1975; Schroeder and Tipton, 1968). This
decrease in soft tissue-lead levels may reflect an atrophy of paren-
chymal cells and an increase in interstitial matter (e.g., fascia,
fat) in these tissues that has been postulated to be a part of the
aging process (Gross et al., 1975; Steiglitz, 1949). Decreases in
bone-lead levels may be due to osteoporosis and/or the reduced lead
exposure of older persons (Gross et al., 1975).
The distribution and kinetics of lead in the body are approxi-
mated by a three-compartment model (Figure 3-1) (Rabinowitz et al.,
1973; 1975). The model is based upon isotopic tracer studies of the
relationships between lead intake, concentration in blood, and
elimination in human subjects; consequently, the three compartments
of the model represent physiological entities rather than distinct
anatomical systems. Aside from blood, the majority of fluids and
tissues of the body cannot be uniquely assigned to individual
compartments.
The blood and certain soft tissues which exchange lead rapidly
with the blood constitute compartment -1. Lead which is absorbed
through the pulmonary and gastrointestinal routes enters directly
into this pool and is subsequently transported within compartment 1,
exchanged with either of the remaining two compartments, or elimi-
nated in the urine. Compartment 2 accounts for a delay in the
labeling of bile and other secretions relative to the labeling of
43
-------
8
u
a
CO
M
H
Eh
o
W
^
a
o
HS
B3
1
W
o
03
-
en
(0
Q
0
O
en
i
Jf*
H
L
1
a
«
a
\O
en
1
Jf
H
J
r
a)
(8
a
^
0
^
_Y*
H
C
41
a
3
S3
>i
O
P3
0
8*
es
r
c
0)
a
3
CO
a
o
a
u
o
94
^
k
C
a
u
3
09
X
T3
Q
39
Q
-------
blood. This compartment, which contains less than half as much lead
as compartment 1,- is thought to represent a portion of the soft
tissue not included in compartment 1 and perhaps the more actively
exchanging skeletal components. Compartment 3 includes the remaining
soft tissue and the majority of the skeletal material. Thus, this
compartment contains most of the body burden of lead.
Of the absorbed lead which reaches the blood, about 46 percent
is subsequently transferred to the other two compartments. A small
fraction of the lead transferred from the blood to soft tissue is
subsequently returned to the blood but the vast majority is elimin-
ated by a variety of pathways. There appears to be no direct
interchange of lead between soft tissue and bone (Rabinowitz et al.,
1973).
Varying estimates of the half-lives of lead in the first two
compartments have been reported in the literature: 27 and 30 days
for blood and soft tissue, respectively, in a 1973 study by
Rabinowitz et al.; and 36 and 40 days in a subsequent paper by the
same authors (Rabinowitz et al., 1975). Regardless of this discrep-
ancy, it is clear that the lifetimes of lead in the two compartments
are quite similar. Furthermore, they are extremely short in
comparison with the half-life of lead in bone, which has been esti-
mated to be about 10^ days (27.5 years). Thus, the body burden of
lead consists of two small and highly transient pools contained in
the blood and soft tissues, and a long-lived, relatively immobile
fraction contained in the skeleton.
While the lead levels in the blood are quite sensitive to varia-
tions in uptake and therefore give a good indication of recent expo-
sure, they provide little insight into a person's lifetime exposure
history. Bone or dentine lead levels are a poor indicator of recent
exposure but a fairly good indicator of lifetime exposure (Gross,
1976; Kehoe, 1969). An accurate chronology of lifetime lead exposure
cannot be inferred from the distribution of lead in bone; however,
45
-------
the concentration and distribution of bone lead does provide a sub-
stantial amount of information. Because of the extremely slow turn-
over of compartment 3, the average concentration in this compartment
more or less reflects a person's average lifetime exposure level
(Barry, 1975). Furthermore, the distribution of lead within the
skeleton is somewhat indicative of the nature of an individual's
exposure history; soft, vascular bones such as the ribs and vertebrae
contain a higher concentration of lead than dense bones such as the
femur, after an acute high-level exposure, and a relatively low lead
concentration following chronic low-level exposure (Kehoe, 1969).
In humans, the adverse toxicological effects of,lead are associ-
ated with the mobile fraction (i.e., that which is contained in com-
partments 1 and 2) (HAS, 1972). The lead outputs from compartment 3
normally represent an insignificant contribution to this mobile lead;
however, under certain circumstances which are not clearly under-
stood, substantially higher quantities of skeletal lead can be remo-
bilized. Large quantities of lead are released from bone during
chelation therapy and abnormal skeletal remodeling resulting from
dietary deficiencies (calcium, phosphate, magnesium) and hormonal
(parathyroid hormone, calcitonin) imbalance (Bethea and Bethea, 1975;
Rosen and Wexler, 1977). Lead in the soft bones is presumably remo-
%
bilized more readily than lead sequestered in the dense bones
(Rabinowitz et al., 1974; Rosen and Wexler, 1977).
In young children the likelihood of one of the aforementioned
nutritional deficiencies (e.g. , calcium deficiency) is very high.
This suggests that children face an increased risk of remobilization
of skeletal lead (EPA, 1977).
3.3 Elimination Characteristics
In adults, approximately 90 percent of ingested lead is elim-
inated in the feces without prior gastrointestinal absorption (Kehoe,
1961; Wetherill et al., 1974). The rate of absorption of lead
46
-------
through the gastrointestinal tract is greater in children (Section
2.1.2), who therefore eliminate a substantially smaller proportion of
their total intake as unabsorbed lead in the feces.
The primary elimination route for lead absorbed by all routes is
in the urine, representing about 95 percent of the total output of
absorbed lead (Rabinowitz et al., 1973). Lead is excreted by the
kidney into the urine, both by glomerular filtration and transtubular
flow (Goyer and Mahaffey, 1972). Renal effects of lead (discussed in
Section 4.1.3) may compound lead toxicity by interfering with urinary
lead excretion. Direct transfer of lead to the urine takes place
solely from compartment 1 (blood), and is the only direct route of
excretion from this compartment.
The remaining 5 percent of the output of absorbed lead is from
compartment 2 (soft tissues) in alimentary tract secretions, hair,
nails, and perspiration (Rabinowitz et al., 1973). The rates and
relative proportion of lead eliminated by all routes appear to be
sensitive both to the dose and the chemical form of the lead,
although these relationships are currently unclear (EPA, 1977).
3.4 Body Burden
A great deal of emphasis has been placed on determining the
human body burden of lead, perhaps because the toxic effects of other
metals, such as cadmium, are directly related to the overall body bur-
den (Friberg et al., 1974). However, the health effects of lead do
not appear to be directly related to the whole body content of lead;
on the contrary, the vast majority of the lead in the body (that
stored in bone) is believed to be essentially inactive (EPA, 1977).
Furthermore, this inactive fraction is- fairly insensitive to short-
term changes in lead uptake, which directly affect health, and thus
the whole body burden can provide a misleading estimate of the
lead-related health hazard.
47
-------
Lead is distributed differentially in the various tissues of the
body. For analytical simplicity, these tissues can be grouped to-
gether on the basis of lead distribution characteristics and the body
burden of lead represented as a limited number of distinct physiolog-
ical compartments (such as the three-compartment model described in
Section 3.2). The lead content of many or all of the tissues is in
constant flux, the magnitude of which can be radically different in
different tissues (Rabinowitz et al., 1973, 1974, 1975; Wetherill et
al., 1974). In the compartmental model, this flux is represented by
rates of input to, transfer between, and excretion from the compart-
ment as a whole.
When the rate of lead intake is constant for extended periods
(-100 days) the concentration of lead in blood reaches an approximate
steady state (Wetherill et al., 1974), presumably indicating an equi-
librium in the overall body burden of lead. Modifications in daily
lead intake, if maintained for a sufficient length of time, will
result in changes in the lead concentrations in the three compart-
ments and the attainment of a new equilibrium condition. The rates
and magnitudes of these changes are dependent upon the rates of lead
flux in the tissues and can theoretically be calculated from the
three-compartment model by' inclusion of the appropriate parameters.
Unfortunately, studies that have experimentally determined these
parameters (Kopple et al., 1976; Rabinowitz et al., 1973, 1974, 1975;
Wetherill et al., 1974) have used a very small number of subjects,
all of whom were adult males, and a limited range of exposure
conditions. Therefore, it is not certain whether these parameters
are applicable to the adult male population as a whole. Furthermore,
given the apparent differences in the behavior of lead in children
and adults, it is almost certain that these parameters are not
applicable to the child population.
48
-------
4.0 TOXICITY OF LEAD
The toxicological impact of environmental lead is a cumulative
product of continuous low-level exposure. The possibility that
adverse health effects may result from chronic exposure from the
ambient environment is of major concern.
Adverse toxicological effects are due essentially to the mobile
fraction of absorbed lead within the body (EPA, 1977; Goyer and
Mushak, 1977). Previously deposited fractions of lead are mobilized
as a result of chelation therapy, normal skeletal remodeling and
metabolism, and periods of physiological stress (Bethea and Bethea,
1975). Normal skeletal remodeling and growth is dependent upon the
levels of parathyroid hormone, calcitonin, calcium, inorganic
phosphate and magnesium (Rosen and Wexler, 1977). By altering the
bodily concentrations of these metabolic factors, dietary metabolic
imbalances (periods of physiological stress) can cause variation in
the blood lead level through bone-lead mobilization.
Two properties of lead are believed to be responsible for wide-
spread adverse health effects. Lead has an affinity for amino acids
containing sulfur, resulting in deformation of protein structure.
Lead also has a tendency to bind to the mitochondria, leading to
interference in the regulation of oxygen transport and energy
generation (Needleman and Piomelli, 1978).
Biochemical impairment of many enzyme systems has been found at
very low lead exposure levels. In fact, recognition of low levels of
exposure is generally a result of biochemical measurements of enzyme
activities (Needleman and Piomelli, 1978). Although lead has been
shown to produce enzyme interference effects at low concentrations,
especially in infants and children, the amount of interference that
can be tolerated by an individual without subsequent harm is uncer-
tain. In vitro and in vivo studies have provided evidence of inhibi-
tory effects at minute blood-lead levels (about 5 iag/dl). It is
49
-------
believed that a "no effect level" of enzyme inhibition by lead is
nonexistent, but the physiological significance of low-level enzyme
inhibition is questionable. Compensation for low lead level enzyme
inhibition is thought to be achieved through a "reserve enzyme capa-
city" but the extent of this low level reserve capacity is as yet
unclear.
A total review of the literature has not been attempted for this
discussion of lead toxicity; rather, a brief synopsis is provided.
More in depth discussions of the health effects of lead can be found
in several publications (e.g., EPA, 1977; WHO, 1977; Kehoe, 1961;
NAS, 1972).
4.1 Biological Effects Associated with Lead Absorption
Lead can affect a number of biological systems in man. The
hematopoietic, nervous, and- renal systems are the most sensitive to
chronic low-level exposure. A number of other systems are also
affected, but to a lesser degree. These include the reproductive,
endocrine, hepatic, cardiovascular, immunologic and gastrointestinal
systems. The discussion of health effects in this report will be
limited to the three systems most sensitive to lead exposure and will
focus on children. The carcinogenicity of lead compounds is also
briefly discussed.
4.1.1 Hematopoietic Effects
Lead inhibits the synthesis of hemoglobin at several points
throughout the heme synthetic pathway (Figure 4-1). Synthesis of
hemoglobin is completed within a few days after the red blood cells
enter the bloodstream; therefore, inhibition of heme synthesis must
take place before this point (Guyton, 1971b). The inhibition of the
enzyme 6-aminolevulinic acid dehydratase (ALAD) is believed to be the
earliest known biological effect of lead intoxication (Hernberg,
50
-------
MITOCHONDRION
KREBS
n
SDCCINYL COENZYME A
+ GLYCINE
CYTOPLASM
CYTOPLASM
J-AMINOLEVULINIC ACID STOTHETASE (ALAS)
5-AMDWLZVULINIC ACID (ALA)
a-AMIHOLEVULINIC ACID DEHTDRAIASE (ALAD)
PORPHOBILINOGEN
1
rail
rciu
i
UHOPORPHYRINOGEN III
tmOGENASE
COPROPORPHYRINOGEN III
COPROGEHASE
MITOCHONDRION
HEME STNTHETASE
PROTOPORPHYREJ IX (PP)
+ IKON + ZINC
HEME ZIHC PROTOPOSPHTRIN DC (2PP)a
GLOBIN
X 1
HEMOGLOBIN
X possible inhibition
X definite inhibition
FIGURE 4-1
SITES OF LEAD INHIBITION IN THE NORMAL PATHWAY
OF HEMOGLOBIN SYNTHESIS
Precise site and mechanism of ZPP formation is unknown.
SOURCE: Adapted from Baloh, 1974; NAS, 1972.
51
-------
1976). A result of this inhibition is a decline in heme synthesis
due to a block in the utilization of 6-aminolevulinic acid (ALA).
However, a decrease in ALAD activity has also been reported for alco-
holics, diabetics, cancer patients and workers exposed to organic
solvents (Yamaguchi et al., 1976) so this cannot be used as a defini-
tive indicator of early lead toxicosis.
The degree of inhibition of ALAD activity increases with
increasing blood-lead levels. Partial inhibition becomes measurable
at blood-lead levels as low as 5 to 10 (u.g/dl (Goyer and Mushak, 1977;
Chisolm, 1971; Wessel and Dominski, 1977). There is no indication
that this partial inhibition is harmful since heme levels are appar-
ently not affected. This suggests an enzyme reserve such as that
discussed in Section 4.0. Above a blood-lead'level of approximately
40 |ag/dl, the increase in ALA excretion is exponential. The inhibi-
tion of ALAD activity accelerates as blood-lead levels increase from
40 to 80 |ig/dl and higher (NAS, 1972). At blood-lead levels between
70 and 90 |ig/dl, ALAD activity is almost totally inhibited (Hernberg,
1976). The relationship between blood-lead levels and ALAD activity
remains constant under varying exposure conditions (i.e., new expo-
sure, steady state, after termination of exposure) (Tola et al.,
1973).
Lead also interferes with the final step in heme biosynthesis,
the chelation of iron by protoporphyrin IX (PP). It is not clear
whether this is due to the prevention of iron passage through the
mitochondrial membrane (Needleman and Piomelli, 1978), interference
with ferrochelatase activity (Lamola and Yamane, 1974), or a combina-
tion of these effects (EPA, 1977). The surplus PP created by the
inhibition of iron chelation does not remain in the unchelated (free)
form, but is chelated with zinc (Zn^+) to form zinc protoporphyrin
IX (ZPP), and bound to globin (Lamola and Yamane, 1974).
52
-------
The elevated levels of PP measured in acidic solvent extracts
of erythrocytes from patients with lead intoxication, led many
investi-gators to the erroneous conclusion that the porphyrin present
in the red blood cells of these patients was free erythrocyte
protoporphyrin (FEP). However, in vivo fluorometric measurements of
whole blood and isolated erythrocytes have demonstrated that the
omnipresent species in lead intoxication is actually ZPP (Lamola and
Yamane, 1974; Blumberg et al., 1977). This view is further supported
by the fact that levels of ZPP measured in whole blood by a
fluorometric technique are very similar to "FEP" levels determined by
extraction methods and show an excellent linear correlation with
these "FEP" values (the coefficients of correlation for linear
relationships between ZPP levels and the FEP levels determined by two
methods were 0.98 and 0.99) (Blumberg et al., 1977). Thus, it is
thought that acidic solvents break down the ZPP chelate complex and
produce the PP found in erythrocyte extracts. FEP values found in
the literature have been reported as "FEP" in this study; however, it
is believed that these values represent an indirect measurement of
the levels of ZPP in the blood, rather than an indication of levels
of free protoporphyrin IX in vivo.
Blood-lead levels in children have been associated with specific
hematologic changes (Table 4-2). At 15 fxg/dl there is a greater than
40 percent inhibition of ALAD activity. At 20 to 25 (ig/dl, there is
greater than 70 percent inhibition in ALAD activity. At 30 to 40
(j.g/dl., urinary excretion of ALA increases above 5 mg/1. At 20 to 25
^g/dl, there is an increase in erythrocyte protoporphyrins. At 40 to
50 (j.g/dl, there is a decreased hemoglobin level (Zielhuis, 1975). An
increase in erythrocytic protoporphyrin is considered to be a sign of
increased physiologic impairment since it is indicative of impaired
mitochondrial function (WHO, 1977).
53
-------
In addition to the enzymatic effects, a shortening of the life
span of erythrocytes has been reported. The mechanisms responsible
for the shortened life span are not clearly understood but may be the
result of several physical effects. Observed effects resulting from
exposure to low levels of lead include an increase in the osmatic
resistance of erythrocytes, an increase in mechanical fragility and
interference with a number of membrane functions, including functions
which are important for maintaining cell integrity (Hernberg, 1976).
The end result of the enzymatic as well as the physical effects
on the hematological system is anemia, resulting from decreased
erythrocyte production and increased cell destruction. This anemia
is often the earliest manifestation of chronic and acute lead poison-
ing and is characterized by increased numbers of reticulocytes and
basophilic stippled cells in the blood. The symptoms of this anemia
are pallor, waxy sallow complexion, fatigue, irritability and head-
ache; irritabillity and decreased play activity may be signs in young
children (NAS, 1972). It is believed that iron-deficient children
may be more susceptible to the toxic effects of lead (NAS, 1972).
In one study, the incidence of anemia rose sharply in children
as the blood-lead level increased from 37 to 100 p.g/dl. At blood-
lead levels below 36 jj.g/dl, 14 percent of the children were anemic,
compared to 36 percent with levels between 37 and 60 |j.g/dl (Betts at
al. , 1973). However, the degree of anemia correlates poorly with
blood-lead levels and does not become obvious until the level exceeds
80 Hg/dl (Hernberg, 1976). In children, a threshold blood-lead level
for anemia is about 40 ^g/dl while for adults 50 (ag/dl is considered
the threshold level (EPA, 1977).
4.1.2 Central and Peripheral Nervous System Effects
There is a great deal of concern over the neurological effects
of lead. Some segments of the population, especially children, may
be exposed to lead in quantities sufficient to cause neurological
54
-------
and behavioral impairment, although the actual levels necessary to
produce such effects are in question (EPA, 1977). It is not known
whether central nervous system (CNS) impairment can occur at levels
below those which produce observable effects in the hematopoietic
system (Damstra, 1977).
Central Nervous System: Accumulation of lead in the body can
lead to severe effects on the central nervous system. These central
nervous system effects are most responsible for the morbidity and
mortality associated with lead poisoning. Symptoms of neurological
changes include ataxia (muscular coordination failure), clumsiness,
weakness, stupor, coma and convulsions (Hahaffey, 1977).
The most severe effect of lead intoxication on the central ner-
vous system is acute encephalopathy (degenerative brain disease).
Blindness, mental retardation, behavior disorders and death can
result at this level of toxicity (NAS, 1976). The pathological
changes may remain after therapy (Mahaffey, 1977) and can be con-
sidered irreversible. In an early, mild form, the subclinical signs
of encephalopathy include psychomotor disturbances, impairment of
intelligence functions and personality changes. Massive doses of
lead corresponding to blood levels above 150 fig/dl are required for
the development of acute encephalopathy. As the disease worsens,
cerebral edema develops (Hernberg, 1976).
Chronic exposure to lead can produce a progressive mental deter-
ioration in children. This is characterized by loss of motor skills
hyperkinetic and aggressive behavior, and convulsions, and has been
associated with blood-lead levels in excess of 60 (J.g/dl (EPA, 1977).
There is a great deal of controversy concerning the subtle
neurobehavioral effects of low-level lead exposure in asymptomatic
humans. It appears that medically significant effects can be
55
-------
produced in adults from exposures yielding blood lead levels below 80
p.g/dl. In children, lower levels (i.e., about 40 (j.g/dl) are believed
to produce neurological damage, possibly because of the
underdeveloped state of the central nervous system (EPA, 1977).
The frequency of neurologic effects appears to increase in
children at blood-lead levels in the range of 50 to 60 ng/dl or above
(NAS, 1976). Although this produces no major clinical effects, it
has been argued that no damage to the central nervous system should
be accepted. Central neruous system damage is believed to be more
serious than the reversible effects on other systems7' since the
nervous system has a poor regenerative capacity (Seppalainen et al.,
1975).
Subclinical effects on intelligence and behavioral activity have
been reported in children with blood-lead levels below 40 (o.g/dl
(Goyer and Mushak, 1977). Exposure to concentrations below those
levels which produce irreversible neurological dysfunctions has been
postulated to be involved in the production of hyperactivity and fine
motor deficits in children (Manaffey, 1977). However, the view that
these behavioral deficits are, or are related to, the cause of ele-
vated blood-lead levels in these children is also tenable. In one
study, the mean blood-lead level in 54 hyperactive children was 26.2
|j.g/dl while the mean blood-lead level in 37 controls was 22.2 p.g/dl
(David et al., 1972). Failure on fine motor tests occurred almost
twice as frequently and mean IQ scores were significantly lower in
children with blood-lead levels 2.40 (ig/dl or those with blood lead
2.30 |ig/dl having radiographically visible lead lines in the long
bones than in controls (de la Burde and Choate, 1972; 1975).
Although many studies have been conducted to test low-level lead
effects on the CNS, no conclusive evidence has been presented. It
remains unknown whether psychological, emotional and neurological
sequelae occur in asymptomatic children with blood-lead levels below
those jassociated with clinical lead poisoning.
56
-------
Peripheral Nervous System: In addition to the effects on the
central nervous system, peripheral neuropathy due to lead poisoning
has been reported. Peripheral nervous system paralysis is character-
ized by selective involvement of motor neurons and is manifested as
weakness of the extensor muscles. At blood-lead levels of 80 to 120
p.g/dl, a slowing of the conduction velocity of the nerves of the
upper limbs and electromyographic abnormalities have been reported
(Hernberg, 1976).
Although peripheral neuropathy is considered rare in childhood
lead poisoning, it has been suggested that this is because the
effects are overshadowed by the clinical symptoms of encephalopathy.
Feldman et al. (1973) observed a statistically significant (p <
0.002) decrease in peripheral nerve conduction velocity in a. group of
24 children with blood-lead levels of 40 (Jig/dl or greater. In
studies involving lead workers with mean blood-lead levels of 40 + 9
H-g/dl, a slowdown of nerve conduction velocity in the upper
extremities and electromyographic abnormalities (i.e., fibrillations
and diminished number of motor units on maximal contraction) were
reported (Seppalainen et al., 1975).
4.1.3 Renal Effects
There appear to be two distinct renal effects from chronic lead
exposure, reversible proximal tubular damage and progressive, irre-
versible renal failure. Although dose-response relationships have
not been defined, it appears that the effects occur only at levels
above those which affect heme synthesis (Hammond, 1977).
Renal tubular dysfunction is manifested in children as Fanconi's
syndrome, characterized by glycosuria (presence of abnormal amounts
of glucose in urine), hypophosphatemia (an abnormally decreased
amount of phosphate in the blood) and aminoaciduria (presence of
amino acids in the urine). Aminoaciduria reportedly results from
57
-------
blood-lead levels above 80 H-g/dl (Chisolm, 1962); however, the exact
level which produces this effect is unclear. The Fanconi syndrome
has been reported in one-third of the children in one study with
acute encephalopathy and blood-lead levels above 150 |J.g/dl (HAS,
1972).
Studies indicate that chronic kidney damage is the result of
high renal lead content for long periods of time. There is no evi-
dence to suggest that kidney damage occurs in asymptomatic cases;
effects only occur in association with other symptoms of lead tox-
icity (Damstra, 1977).
Prolonged and excessive exposure to lead can result in chronic
lead nephropathy, although the level of exposure which causes this
effect is not known (Hammond, 1977). Chronic lead nephropathy, a
progressive and irreversible disease, is characterized by progressive
azotemia (presence of urea in the blood), interstitial fibrosis, tubu-
lar degeneration and glomerular vascular changes in small arteries
and arterioles of the kidney (Morgan et al., 1966). Renal insuffi-
ciency may be a sign of subclinical lead poisoning (Campbell et al.,
1977). Renal failure may result from more extensive exposure (EPA,
1977).
The formation of inclusion bodies, composed of a lead-protein
complex containing approximately 50 M-g lead/mg protein (Moore et al.,
1973), is one of the earliest effects of lead nephropathy (Hernberg,
1976). These inclusion bodies appear in renal proximal tubular cells
as well as in other tissues (Hammond, 1977). The lead in the inclu-
sion bodies is 60 to 100 times more concentrated than in the whole
kidney (Goyer and Mushak, 1977). These inclusion bodies may serve as
a defense mechanism by binding the lead and thus lowering the
concentration of lead in the cytoplasm (Goyer and Chisolm, 1972).
Chronic renal injury from lead exposure can also produce gout
(Emmerson, 1968). Although the mechanism of interference with uric
58
-------
acid excretion is not known, it has been hypothesized that the rise
in the serum urea level may result from a loss of gloraeruli, leading
to a reduction in. the glomerular filtration rate (Campbell et al.,
1977).
High levels of lead in drinking water OlOO |J.g/l) have reported-
ly been responsible for renal failure, hyperuricemia and gout in
individuals drinking the water for 15 to 30 years (Beattie et al.,
1972).
4.1.4 Carcinogenicity
A relationship between lead exposure and cancer in humans has
not been demonstrated. However, very high doses of lead salts have
been shown to be carcinogenic in laboratory animals by a number of
investigators: lead phosphate in rats (Zollinger, 1953; Roe et al.,
1965; Sunderman, 1971) and mice (Sunderman, 1971); lead acetate in
rats (Boyland et al., 1962; Zawirska and Medras, 1968; Kanisawa and
Schroeder, 1969; Sunderman, 1971; Coogan, 1973; Stiller, 1973) and
mice (Van Esch and Kroes, 1969; Sunderman, 1971); and lead subacetate
in rats (Van Esch et al., 1962; Mao and Molnar, 1967; Oyasu et al,,
1970; Sunderman, 1971) and mice (Van Esch and Kroes, 1969). Tumors
of the kidney, both benign and malignant, were produced in all of
%
these studies, regardless of the route of adminis\ration (orally in
food or water, or by intraperitoneal and/or subcutaneous injection).
High incidences of tumors of the testes, adrenal, thyroid, pituitary,
prostate and lung have also been seen in rats and mice receiving
these' salts (Zawirska and Medras, 1968; Sunderman, 1971), and cere-
bral gliomas have been observed in 2 rats out of 17 receiving dietary
lead subacetate (Oyasu et al., 1970).
In contrast to the animal data, no significant relationship be-
tween exposure to lead and cancer in a human population has been
reported. Dingwall-Fordyce and Lane (1963) conducted a follow-up
study of 425 persons who had been exposed to lead in a storage bat-
tery factory. No evidence was found to suggest a correlation between
59
-------
lead absorption and malignant disease. In a more recent study
(Cooper and Gaffey, 1975; Cooper, 1978), the incidence of death from
malignant neoplasms among battery plant workers and from lung cancer
among smelter and battery plant workers was slightly higher than
expected, although this increase was not statistically significant.
A consistent feature of the animal studies is that the animals
were subjected to very large quantities of the lead salts utilized.
The lowest dietary concentration of a lead salt which produced cancer
in the feeding studies was 0.1 percent. In the injection studies,
the lowest lifetime dose received by rats that developed renal tumors
was 120 mg. IARC (1972) noted that the level of human exposure
equivalent to the intake of lead acetate that has produced renal
tumors in rats is 810 mg/day (550 mg Pb/day). This level greatly
exceeds that at which severe, debilitating effects and even death
will be produced. Thus, even if lead is a human carcinogen, the car-
cinogenic effects will presumably be greatly overshadowed by the sys-
temic toxic effects at the exposure levels generally encountered.
Carcinogenicity cannot be considered a singular risk associated with
lead exposure since the systemic effects constitute a major public
health problem.
«
4.2 Indices of Exposure/Effect
There are many tests which can be used for the detection of in-
creased lead absorption. Tests which measure both tissue lead con-
tent and tissue metabolic effects are available. However, no single
test can be used for the determination of body burden or total meta-
bolic effects. At present, blood-lead concentration is considered
the best available measure of tissue lead content, while free
erythrocyte protoporphyrin (FEP) concentration is the best measure of
tissue metabolic effects (Baloh, 1974).
60
-------
4.2.1 Lead Levels in Tissues
The concentration of lead in several tissues has been used to
indicate an individual's past exposure history to lead. Although
blood-lead content is the most widely used criterion, tissues, urine,
hair, teeth and bone have been sampled.
Blood Lead; The blood-lead level is used both as an index of
exposure and for the diagnosis of health effects. This value is the
most widely accepted measure of recent exposure, as well as repre-
sentative of the actual mobilized fraction of lead responsible for
the toxic effects in the body (Goyer and Mushak, 1977). A blood-lead
level of 40 |j.g/dl is believed to be the maximum level at which no
adverse health effects are found, although changes in enzyme activity
have been observed below this value. Clinical manifestations of lead
poisoning begin when blood-lead levels are consistently above 80
pg/dl (Goyer and Mushak, 1977; HAS, 1976).
Five methods are commonly used for the determination of blood-
lead concentrations: spectrophotometry, flame atomic absorption,
Delves cup, furnace atomic absorption, and anodic stripping voltam-
taetry. These methods reportedly have the capability of producing
results which are valid and reproducible within 5 percent precision
or better. However, interlaboratory comparisons do not appear to
confirm this degree of reproducibility. Discussions of the methods
(Pierce et al., 1976) and the variability of the results of the
methods (Lucas, 1977) have recently appeared in the literature. There
are many sources of variability involved, including sampling
technique, storage time, contamination, and analytical procedure
(Pierce et al., 1976). Studies indicate that up to 80 percent of the
variability can be due to analytical method error (Lucas, 1977).
Because of the wide variation in blood-lead measurements, it is com-
mon practice to run at least two analyses of the same blood sample.
61
-------
Even with these limitations, blood-lead analysis is still the
most widely used test for the diagnosis of increased lead absorption.
Many of the other test methods are based on a relationship to blood
lead.
Urine Lead; Both blood-lead and urine-lead levels are accurate
indicators of recent lead exposure. Urine-lead levels are considered
less accurate in that they are susceptible to changing renal output
or to dilution due to variable water content. In a steady state,
urine lead is representative of blood lead.
A "normal" value for urinary lead in young children is usually
less than 55 )ig/24 hours. However, this value should not be used as
an index of body burden since there can be complicating factors that
affect lead excretion and give a false impression of the amout of
lead in the body (Baloh, 1974).
Hair Lead; Hair lead analysis can be easily performed and can
indicate chronic lead exposure. Since lead reacts with the
sulfhydryl groups in hair protein as the hair emerges from the scalp,
the concentration of lead at different sections can be indicative of
episodic exposures to high lead levels (Goyer and Mushak, 1977).
Contamination of hair by exogenous deposition poses a problem in
evaluating the measurement. Although mean levels in children and
adults are in the range of 20 to 30 |j.g/g hair (Baloh, 1974), appro-
priate precautions (e.g., careful washing of the hair sample) must be
taken if the measurement is to be considered a reasonable indicator
of exposure.
Tooth Lead: Tooth lead analyses have been used to a limited
degree as indicators of past heavy lead exposure. It is believed
that the lead content of the tooth represents the total exposure up
62
-------
to the time of removal. The reliability of tooth lead concentrations
as an indicator of lead toxicity has not been evaluated (Baloh,
1974).
Bone Lead; Bone is an ideal tissue to analyze for total body
burden measurement, since more than 90 percent of the body burden of
lead is deposited in the skeletal system of adults, and 60 to 65 per-
cent is deposited in the bone tissue of children. However, the value
of such a determination is questionable since this bound lead is very
slowly mobilized and does not represent a great danger. Correlation
of bone-lead levels to the manifestations of toxic symptoms cannot be
made, although bone-lead levels may single out those individuals
highly susceptible to lead toxicity (Goyer and Mushak, 1977).
Multiple bands of increased density in growing long bones (as seen by
radiographic examination) indicate prolonged, increased absorption of
lead (NAS, 1972).
4.2.2 Metabolic Effects Associated with Lead in Various Tissues
It appears from the literature that there is a trend toward put-
ting more reliance on measurements of metabolic effects associated
with absorbed lead in tissues rather than on blood-lead values.
While the blood-lead level is considered a reliable index of recent
lead exposure, it does not necessarily indicate the extent of lead-
induced toxic effects. For this reason, considerable attention has
been focused on measurements of the levels of intermediates and
enzymes of the heme-synthetic pathway in the blood. Variability
associated with blood-lead measurements has provided additional
impetus for finding direct indices of-lead toxicity. However, until
these new methods have been tested and approved, blood-lead values
will continue to be the most widely used measurement. Some of the
tissue metabolic effects measurements have been correlated with
blood-lead values. A table (Table 4-1) showing these reported asso-
ciations follows the discussion.
63
-------
Tissue effects measurements include free erythrocyte protopor-
phyrin (FEP) and zinc protoporphyrin (ZPP) determinations, urine
coproporphyrin (COPRO) measurement, urine 6-aminolevulinic acid (ALA)
determination, and 6-aminolevulinic acid dehydratase (ALAD) activity
measurements. These determinations are useful in detecting the sub-
clinical effects of lead on hemoglobin synthesis. Since lead inhib-
its several enzymes essential to the synthesis of heme, measurement
of heme precursors in the blood and urine can be indicative of
metabolic effects associated with increased lead absorption.
Zinc Protoporphyrin/Free Erythrocyte Protoporphyrin: Zinc pro-
toporphyrin (ZPP) appears in the blood as a result of chronic lead
absorption. Since ZFP fluoresces when excited with high energy blue
light, the compound can be fluorometrically assayed. A rapid and
reliable test for lead absorption based on this assay has been
devised. This test can differentiate between lead poisoning, iron-
deficiency anemia, and other disorders which may cause a rise in ZPP
levels (Lamola et al., 1975a,b).
Numerous investigators have reported levels of "free erythrocyte
protoporphyrin" (FEP) based upon measurements of free protoporphyrin
IX (PP) in acidic solvent extracts of whole blood and isolated
erythrocytes. However, the presence of PP in these extracts is ap-
parently a. secondary effect of the extraction procedure on the ZPP
present in the erythrocytes (Section 4.1.1), and therefore FEP is
thought to be an indirect measurement of ZPP (Lamola and Yamane,
1974)'.
A recent development has been the design of a portable hemato-
fluorometer which can, in about five seconds, measure ZPP concen-
trations under field or laboratory conditions from a single drop of
whole, unprepared blood. This appears to be a highly effective and
efficient means of detecting the early signs of lead absorption and
64
-------
and could be useful as a mass screening technique. A discussion of
this instrument has recently appeared in the literature (Blumberg et
al., 1977).
Urine Coproporphyrin: Coproporphyrin (COPRO) measurements are
considered less specific than FEP measurements. Coproporphyrin
excretion begins to increase at approximately 35 to 40 H-g/dl blood-
lead levels, but can be affected by conditions other than lead expo-
sure. Hepatic disorders, rheumatic fever, poliomyelitis, infectious
mononucleosis, and alcoholism can all increase the COPRO level in
urine (Baloh, 1974).
Both sample collection and analysis of the COPRO test are sim-
ple. An approximate upper bound to the normal excretion rate for
both adults and children is 0.2 )ig/ml urine (Baloh, 1974).
6-Aminolevulinic Acid; Increased levels of 6-aminolevulinic
acid (ALA) in urine have been associated with blood-lead levels of 40
to 50 H-g/dl in adults (Hernberg et al., 1970). Since levels of
concern can be below this, the concentration of ALA in urine is of
limited utility. An upper normal level of excretion is difficult to
define. Since the rate of both false negatives and false positives
is high, the ALA test is not recommended for mass screening programs.
6-Aminolevulinic Acid Dehydratase: A more sensitive index of
low level lead absorption is ALAD activity. This test can detect
changes in lead concentrations down to blood-lead levels of approxi-
mately 5 fig/dl (Hernberg et al., 1970). This test is believed to be
the most sensitive indicator of biological effect. It has the advan-
tage of showing changes in lead absorption in asymptomatic humans
(Goyer and Mushak, 1977). Although partial inhibition of ALAD activ-
ity does not cause any adverse health effects, presumably due to a
large reserve capacity, it is reflective of early biochemical altera-
tions at low ambient environmental levels (Hernberg, 1976).
65
-------
The correlation of ALAD to blood-lead level is very good (Tola
et al., 1973). Because of this close agreement, ALAD can be used to
predict blood-lead values.
4.2.3 Other Indices
Although not useful for monitoring or screening purposes, other
indices can be used to assess lead absorption. Nerve-conduction
velocity measurement can be a useful neurological test to detect
early signs of lead exposure (Seppalainen et al., 1975; Singerman,
1976). Renal function tests and electron microscopic examination of
the characteristic inclusion bodies are other possible measures of
lead exposure (Task Group on Metal Toxicity, 1976). However, since
renal function and nervous system damage are not evident before clin-
ical symptoms appear, the determination of hematological changes
remains a more useful tool for early detection of exposure
(Singerman, 1976).
4.3 Effects Levels
Specific toxic effects of recent lead exposure in humans are
characteristic of exposure levels. These effects levels can be mea-
sured by many physiological indicators. Blood-lead levels are the
most commonly reported index of the extent of recent lead exposure
and of the active toxic fraction of lead in the body.
There is a positive correlation between blood-lead levels of >_
30 p.g/dl in adults and anemia and neurological impairment. Similar
effects are seen in children with blood-lead levels of >__ 50 to 60
|ig/dl (NAS, 1976). The more subtle manifestations of subclinical
behavioral dysfunction (e.g., hyperactiyity, slowed learning ability)
are not directly measurable by neurochemical tests, but are estimated
with functional tests and correlated with hematopoietic chemical
66
-------
pa
I
w
u
PQ
w
i
cu
M
33
CO
a
o
M
3
w
OS
H
03
Cd
H
*
r"1
«
IJ
4)
(4
rH
3
m
CD
,_)
3
»rt
v '
rt
.0
p^
H
O
3
"4*
^sT ^^
m PN,
r*^
0
H 0
O
O M
r^ ^^^
ta
X-V
TJ O
1 O
i«
rH
PU T3
M 'ao
^
o
rH
a,
04
m
rH
§
A
rH
Ct)
. O
00 rH
N-'^
Pk -0
N ^60
"^
00s'
o
rH
cx,
fL>
N
o"
rH
rH
CO
4J
CU
00
M
CU
"c
)4
38
pa
CU
CO
rH
0
C5
1
.3.
r-.
CM
CM
11 ^^^
U
c5
II
3^
CO
J-l /-\
H T3
C 0
3 0
' rH
0 rH
< -O
^ 00
a.
o
rH
^
j_j
67
-------
measurements of the hemoglobin enzyme system. Since blood oxygen-
carrying capacity is effectively lowered with the onset of the
inhibition of heme production, CNS degradation is expected to paral-
lel heme inhibition, because of the extreme sensitivity of the CNS to
hypoxia.
In vivo and in vitro studies reveal inhibition of ALAD at levels
as low as 5 |ig/dl (Hernberg et al., 1970; Chisolm et al., 1975), but
it is believed that there is no complete absence of the enzyme-
inhibitory effect of lead at any level (Wessel and Dominski, 1977).
This may be compensated for at low lead levels by a reserve enzyme
capacity, but the individual effective range of this reserve is as
yet unclear. Despite this possible reserve, blood-lead levels of 30
)j.g/dl in women have resulted in definite ALAD inhibition (Hernberg et
al., 1970).
Table 4-2 presents a sample of the reported known low blood-lead
level and acute high blood-lead level effects.
68
-------
TABLE 4-2
CLINICAL SIGNS OF LEAD INTOXICATION
Pb-Blood
Level
5-20
15
25-30
30-50
40-80
Effect
Normal background levels
Partial inhibition of ALAD
activity but no measurable
increase in -ALA excretion
Threshold level for in-
crease in EP.
Increase in protoporphyrin
concentration in women and
children
Deleterious effects on red
blood cells (change in osmotic
resistance and mechanical
fragility)
FEP elevation of diagnostic
importance
Potential danger to children
Firs't detectable increase in
ALA excretion and FEP levels
in body fluids; anemia
Increase in protoporphyrin
concentration in men
Decreased ALAD activity
Decreased ALAD activity
Increase in urinary ALA, CP
Increase in FEP
Reticulocytosis
Nerve conduction effects
Inclusion bodies
Adverse metabolic effects on
heme synthesis, early mild
symptoms of plumbism
Slight drop in hemoglobin level
Anemia
Reference
King (1971); Jenkins
(1976)
Jenkins (1976)
Piomelli (1978)
Hemberg (1976); NAS
(1976)
Hemberg (1976)
Pioaelli et al. (1973)
Center for Disease Control
(1975)
Jenkins (1976)
Hemberg (1976)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Jenkins
(1976)
(1976): NAS
NAS (1976)
NAS (1976)
69
-------
'TABLE 4-2 (CONCLUDED)
Pb-Blood
Level
>80
Effect
Increased risk of acute and
chronic clinical effects
» Obvious anemia
Reticulocytosis becomes
measurable
Shortening of erythrocyte life
span
Decreased ALAD activity
Fivefold increase in urinary
ALA, CP
Increase in FEP
Anemia
Ataxia, coma, convulsions
Fanconi syndrome, chronic
nephropathy
Acute neurological disorders
Reference
NAS (1976)
NAS (1976)
Hernberg (1976)
Hernberg (1976)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
Goyer and Mushak (1977)
70
-------
5.0 SENSITIVE POPULATIONS
Two subgroups within the general population have been identified
as more sensitive and at greater risk to environmental lead ex-
posure than the average adult. Children under the age of four are
especially susceptible to the toxic effects of lead. Fetuses have
also been identified as a sensitive population and the pregnant
female as their exposure vehicle based on the fact that the fetus is
exposed to lead via transplacental absorption.
5.1 Children
Children are known to be especially susceptible to acute and
chronic lead poisoning. Empirical evidence indicates that children
tend to become exposed to and absorb greater quantities of lead than
do adults. In addition, clinical studies demonstrate that young
children are much more likely to suffer ill effects from lead expo-
sure than adults. The following paragraphs support the contention
that children (from 1 to about 4 years of age) should be considered
the critical receptor to environmental lead exposure and that
regulatory actions should incorporate suitable safety factors during
standard-setting procedures.
5.1.1 Increased Potential for Exposure to Lead
There is an increased hazard to children from the ingestion of
lead-contaminated materials. Normal hand-to-mouth activity (i.e.,
thumb sucking and finger licking) in young children is a significant
mechanism of lead exposure. Lead contaminated soil and dust is a
primary exposure source for children due to this activity (Lepow et
al., 1974). Juvenile dietary habits are responsible for additional
exposure to lead. These immature dietary habits include the
retrieval and ingestion of dirt- or dust-contaminated foodstuffs (Day
et al., 1975).
71
-------
In addition, there is significant opportunity for increased lead
exposure among children with pica and among children who mouth
foreign objects. Pica, the repetitive ingestion of nonfood items, is
a fairly common behavior pattern among young children. Two studies
(Millican et al., 1962; Barltrop, 1966) have described the incidence
of pica and mouthing behavior in child populations. In both studies,
the incidence rates for pica and mouthing were highest in the youn-
gest children studied (1 to 2 years) and decreased fairly steadily
until 3 to 4 years of age. In addition, both studies reported that
the incidence of these behaviors (particularly pica) in black child-
ren was generally substantially higher than in white children of the
same age. Social, cultural, and economic differences between the
populations almost certainly contributed to this difference. Thus a
physiological etiology for the difference in incidence rates could
not be inferred from these investigations. Among white children 1 to
2 years old, 28 percent had pica and about 82 percent displayed
mouthing behavior; among blacks the rates were 57 and 78 percent for
pica and mouthing, respectively (Millican et al., 1962). Among
children 2 to 3 years old the rates were 20 and 52 percent for white
children and 40 and 62 percent for blacks. The prevalence of pica
among white children was low after age 3 (2 to 4 percent), but among
black children it remained at about 20 percent up to age 6 (Millican
et al., 1962).
Estimates of lead intake by children with pica for paint range
as high as 2.1 rag/day (NAS, 1976), about ten times greater than what
.*
one might expect from normal environmental sources (i.e., 100 to 200
|j.g/day from air, food, and water). Due to the variables involved
(e.g., housing, socioeconomic condition), it is difficult to quantify
the additional lead intake by children with pica, for the infant
population in general, or for specific subsets within that popula-
tion. It is obvious, however, that in certain instances, children
72
-------
with pica for paint can absorb lead in amounts significantly greater
than normal.
Respiratory characteristics of the child impose a greater poten-
tial for inhalation of airborne lead than those of the adult. Chil-
dren take part in greater physical activity than adults, thereby
increasing their air intake, and breathe more through the mouth (due
to greater physical activity and more frequent respiratory infec-
tions) thus employing a less effective filtering mechanism (American
Lung Association, 1978).
The child has an enhanced risk of exposure to lead via inhala-
tion since concentration gradients for airborne lead increase as one
approaches ground level (Jenkins, 1976). Vehicular exhaust, a low
altitude source of airborne particulate lead, is a major contributor
to the inhaled component of lead uptake in the child living in close
proximity to heavily trafficked areas (NAS, 1972; Angle and Mclntire,
1975). The child is also exposed to lead from dust that is resuspen-
ded by vehicular traffic (Jenkins, 1976). Resuspension is dependent
upon vehicle speed. A range of 1 to 5 percent resuspension of depos-
ited particulates by passing vehicles has been estimated (Sehmel,
1976).
5.1.2 Metabolic Differences
Children appear to have a gastrointestinal lead absorption rate
that is four to five times higher than that of adults (Mahaffey,
1977; Alexander, 1974; NAS, 1976). This increased absorption rate,
coupled with the potentially higher exposure dose (as a result of
pica) can result in much higher blood-lead levels than expected in an
adult.
The daily uptake per unit body weight in children far exceeds
that in adults. It should be noted that the studies showing roughly
equivalent blood-lead concentrations in children and adults do not
necessarily refute this point, since a child may be able to assim-
ilate blood lead into the soft tissues and bone at a more rapid rate
than an adult (Jenkins, 1976).
73
-------
The relative proportion of the lead body burden in the slow
exchange pool (i.e., in the dense bone matrix) is smaller in children
than in adults. Only 60 to 75 percent of the lead body burden is
located within a child's skeletal system, compared to 90 percent or
more in the adult (Barry, 1975; EPA, 1977). This suggests that a.
larger amount of the absorbed lead can be concentrated in the soft
tissues, where it may reach toxic concentrations. For example, brain
tissue in neonatal rat tends to concentrate lead to a greater degree
than in adults (HAS, 1976).
Mechanisms for elimination of heavy metals are not well
developed in the young, and this may ultimately result in higher soft
tissue lead burdens in children than in adults at the same rate of
lead uptake (per unit body mass). Studies have indicated that
blood-lead levels in immature and adult rats were comparable after
acute lead exposure, but were sustained longer in the immature rat
(Bayley and Brown, 1974).
5.1.3 Inherent Physiological Sensitivity
Studies in both laboratory animals and children have shown that
the brain is highly vulnerable to irreversible damage during infancy
and early childhood because of rapid growth rate of this organ (NAS,
1976). Due to this immature developmental state, infants may be
especially sensitive to the detrimental effects of lead exposure.
The infant's higher susceptibility is due in part to the rapid
growth rate characteristic of organogenesis. Organ formation occurs
from the second trimester of pregnancy through the fourth year
postpartum. This period of rapid growth and increased stress
sensitivity is considered the "growth -spurt" (NAS, 1976).
In humans the growth spurt is defined in terms of three brain
components. Glial replication and differentiation continue through
the first eighteen months after birth. Myelination extends through
74
-------
the third and fourth years. Cerebellar growth extends through the
eighteenth month postparturn and is most rapid during this period
(NAS, 1976). This rapid growth rate increases susceptibility to a
variety of stresses such as nutritional deficiencies. Studies of
infants with pyloric stenosis have shown that the brief starvation
period encountered had permanent effects on their learning abilities
and general adjustment ability 5 to 14 years later (Klein et al.,
1975). Reduced IQ levels have been demonstrated in school age
children who had experienced malnourishment during the initial two
years postpartum (NAS, 1976).
Long-term behavioral deficits were demonstrated in neonatal rats
receiving oral administration of lead (Sabotka and Cook, 1974).
Study groups of asymptomatic children with a history of pica for
paint displayed poor learning ability, seizures, and hyperactivity
(de la Burde and Choate, 1972). Similar findings are reported for
symptomatic children (Byers and Lord, 1943).
5.2 The Fetus and Pregnant Woman
Physiological sensitivity to lead may be at a maximum during
fetal development. The pregnant female must be recognized as the
exposure vehicle for the fetus since the placental transfer of lead
is the main route of fetal lead uptake. In addition, the pregnant
female may herself be more sensitive to lead due to increased food
intake and changes in hormonal status. Hormonal imbalances which
result from pregnancy (Guyton, 197la) may influence the mobilization
of lead from bone.
5.2.1 Placental Transfer
Lead has been shown to cross the placental barrier in laboratory
animals (Kostial and Momcilovic, 1974; McClain and Siekierka, 1975)
as well as in humans (Baglan et al., 1974; Gershanik et al., 1974).
There does not appear to be any significant difference between
maternal and fetal blood-lead levels at any time during pregnancy
75
-------
(Gershanik et al., 1974), although placental blood-lead levels may
be slightly (but not significantly) higher than levels in maternal or
fetal blood (Baglan et al., 1974; Harris and Holley, 1972). Lead has
been detected in the fetus as early as the twelfth week of intrauter-
ine life and has been shown to increase throughout gestation. The
lead content of the fetus at birth has been recorded as 300 |j.g; the
equivalent of the daily intake for the normal adult (Barltrop, 1977).
The transplacental passage of lead in blood is particularly
important for two reasons. The fetus is highly sensitive to the
neurological effects of lead exposure (due. to lack of blood-brain
barrier, efficient absorption, and rapid brain growth rates).
Additionally, the newborn is starting life with a significant
"background" blood-lead level. The observed positive correlation of
urinary ALA levels with blood-lead levels in newborns indicates that
heme-biosynthetic derangement must have begun in utero (EPA, 1977).
Exposure of pregnant women to high water-lead concentrations has been
correlated with the higher blood-lead concentrations in their men-
tally retarded offspring (Moore et al., 1977). This reinforces the
association between lead exposure during pregnancy and subsequent
neurological damage to the fetus, but the specific exposure, absorp-
tion, and retention levels and their corresponding specific effects
are as yet unknown.
5.2.2 Inherent Sensitivity; Immature Organogenesis
The fetus displays an immature developmental state, as well as a
lack of development of a blood-brain barrier (Bridbord, 1978). The
uptake (absorption) of lead has been shown to be six to eight times
greater in the brain of suckling rats than in the brain of adult rats
(Momcilovic and Kostial, 1974). Krigman and Hogan (1974) observed a
fourfold increase of lead uptake in the brain of suckling rats as
76
-------
compared to adults. The immature state of the fetal brain, central
nervous system, and elimination systems results in increased
sensitivity to very low concentrations of lead. In humans,
neurological development seems most pronounced from the second
trimester of pregnancy until several years after birth (NAS, 1976).
Permanent neurological damage may result if the individual is
stressed during this sensitive span. The lack of development of the
blood-brain barrier, in combination with the increased permeability
of cerebral capillaries in the fetus, amplifies the sensitive state
already created by immature brain-tissue development. Thus, while
the brain and central nervous system of the fetus are inherently
sensitive to concentrations which are nontoxic to mature systems,
they are also prone to increased deposition of lead.
Rapid brain growth rates of infants create a greater risk of
lead-induced neurologic damage. This rapid growth rate takes the
form of the growth spurt in humans, occurring during the second
trimester of pregnancy, through the initial four years postpartum.
Permanent adverse effects on learning ability can result from the
impact of lead on the brain during this growth spurt (NAS, 1976).
Behavioral abnormalities (i.e., hyperactivity, aggressiveness, trem-
ors and repetitive grooming behavior), have been produced in rats
exposed to lead during the growth spurt period (Michaelson and Sauer-
hoff, 1974). Suckling rats fed maternal milk dosed with lead during
postnatal days 1 through 10 showed significantly slower learning than
those fed equal doses of lead during days 11 through 21 (Brown,
1975).
5.3 Threshold Levels
Threshold-lead levels are defined as those minimum blood-lead
levels capable of inducing toxic response. In attempting to define a
safe threshold level in terms of blood-lead levels, the most phys-
iologically receptive (sensitive) population to augmentations in this
77
-------
level must be singled out and labeled as the highest risk group. The
maximum safe threshold level must also accommodate variations in
individual responsiveness to this lead level.
Due to higher lead absorption rates, unique sources of exposure
and lack of mature development of excretory systems (yielding higher
pooling in target tissues), fetuses and young children are the most
physiologically receptive and sensitive individuals. Therefore, in
defining a threshold level for lead, the lowest known toxic levels
affecting this portion of the human population should be used. A
suitable margin of safety must be incorporated into the determined
threshold toxic effects level when setting any environmental
standard. A conservative margin of safety should be employed in
defining the allowable limits of exposure for the developing fetal
central nervous system due to the proven neurotoxicity of lead (EPA,
1972a).
ZPF elevation and corresponding impairment of heme synthesis at
blood-lead levels above 30 ug/dl are regarded as unsafe for children
and unacceptable by EPA (1978b). There are, however, contrasting
opinions as to the actual impact of a rise in ZPP levels. ZPP ele-
vation may not indicate insufficient heme or hemoglobin production,
although it does indicate an interference in the heme synthetic
pathway. The rise in ZPP may be caused by other factors such as iron
deficiency (EPA, 1978b).
The Center for Disease Control (1975) set the level of signifi-
cant danger to children at 30 fig/dl, and considered FEP levels to be
of significant diagnostic importance. The level of 30 (j.g/dl set by
the CDC is endorsed by the American Academy of Pediatrics and is now
the target level set by EPA (1977) at which undue lead exposure
begins.
Although the maximum safe lead level has been set at 30 fj.g/dl by
CDC, retrospective studies indicate that hyperactivity and altered
motor activity may be correlated with blood-lead levels in children
78
-------
having blood-lead levels lower than 30 (jig/dl. These studies suggest
that blood-lead values in the 25 to 30 ng/dl range may initiate toxic
effects in children but this position is based on the tentative
hypothesis that lead is the cause of hyperactivity and altered motor
activity in these children; in fact, this behavior may be the cause
of or be correlated with the cause of the elevated blood-lead levels.
Increased FEP levels have been recorded in women and children at the
25 to 30 jjig/dl level (HAS, 1976; Zeilhuis, 1975).
79
-------
6.0 SOURCE CONTRIBUTIONS TO DAILY LEAD UPTAKE IN HUMANS
The method employed in this study to estimate the degree to
which each major environmental source of lead exposure contributes to
an individual's total daily lead uptake is based on probable exposure
conditions (i.e., ambient lead levels) as well as individual biologi-
cal absorption rates for each exposure route. The method consists of
a five-step process:
definition of ambient concentrations of lead for the major
exposure sources (i.e., air, food, drinking water, soil/
dust, paint)
determination of daily lead intake according to the
relationship:
where 1^ is the daily lead intake from source i (e.g., air,
food, drinking water, paint, soil/dust), C^ is the consump-
tion per day of each lead source i and [Pb]£ is the concen-
tration of lead in each source i
calculation of the amount of lead absorbed from each exposure
source i:
where U^ is lead uptake for each exposure source i, 1^ is
the daily lead intake from each source i, and A£ is the
percent absorption of lead, via the appropriate exposure
route, for the particular source.
calculation of the total lead uptake from all sources, Ut:
Ut - S(li Ai) =ZUi
determination of the proportion (P^) of total daily uptake
(Uj-) provided by each of the five possible exposure sources
(i.e., source contribution factors):
Ui
Pi = - - 100
80
-------
6.1 Basic Assumptions
Certain assumptions are required to define the amount of each
source material consumed per day. Where appropriate, Reference Man*
values are utilized for daily air and food consumption rates (see
Table 6-1). Daily consumption rates for drinking water are those
values suggested by NAS (1977) as conservative estimates.
Hand-to-mouth activity (e.g., thumb sucking and finger licking)
resulting in the ingestion of soil/dust is a normal behavioral char-
acteristic of children through five years of age (Piomelli, 1978).
Within a lead-contaminated environment, hand-to-mouth activity and
immature dietary habits (i.e., the retrieval of food from dusty
surfaces or soil, and subsequent consumption), make soil/dust a major
source of ingested lead for children. Under average urban conditions
(after thirty minutes of normal playground activity) 5 to 50 mg of
dirt from a child's hand can be transferred to a typical "sticky
sweet." Ingestion of 2 to 20 sweets could result in an intake of 100
mg of soil/dust or more (Day et al., 1975). A small child playing in
dirt easily ingests 10 mg of soil/dust with each episode of
hand-to-mouth activity. A conservative estimate of ten hand-to-mouth
activitites a day would result in the ingestion of 100 mg of
soil/dust a day (Lepow et al., 1974). Therefore, 100 mg per day
would seem to be a reasonably conservative assumption for the
ingested soil/dust of the two- to three-year-old.
Pica occurs to some degree in a substantial percentage of chil-
dren between 12 and 36 months of age (NAS, 1976). Children exhibi-
ting pica for paint are of major concern, because of the high levels
of lead in some paints, with older painted surfaces containing lead
in concentrations greater than 1 percent. Pica for paint is believed
*From the ICRP Reference Man tables (International Committee on
Radiological Protection [ICRP], 1975).
81
-------
3
i-* «fi
« Z
it
u 5
a a
i!
M
u a
35
u
01
14 U*
* CU
Is
Si,
32
« a
<% a
£ 2
*4 U
w >
5 u
o 3
M
W 41
32
" "3
3 IS
a I
8 2M
a «
M a IH
54) j
M
.' a*
41 i-l
H 4J
S 3
w u
a
a
«J U
a eo
3 1
4* 4
a
d lu FDA ti
upacional.
*4 O
o _ u
M^? O
T5 B
oo^< a
g§>-
«MU
M
Sag
" 3 *
4) .C
SB*
T» u "*
o 4) a
Jos
2a
M 41
0.2!
<2 3
i i
x x
a a
g u
I «
.f":
n* »
t c>4
S
a
o
o
u
a
a
a
1-1
o
u
I
M
V
A
3
1
3
0
u
X
1
01
O
<44 41
4,3
K
4 O
41 5
«4
>8
4§
U M
41 -rt
3|
1
X X
a a
o -o
^ x ^>
o x a a
a « -^« 33
a^ii 2
41 0 «
*i "«mn w
o|^ *
«
3
1
^ a
| S
3 ^
* 3
« 5
3 «
2
as
M
a
§
a
41
T)
iH
a
u
o
4*
1
2
rs
f-i
u
o
o
u
B
X
3
w
8
u
a.
1
^
*
a
*w
i
S
u
1
CO
a
c
4
1
O
r*
a
e
u
o
3
41
C
a
a
41
3
r-4
a
3?
r*
en
&
U
h*
§
4)
CO
3
w
u
1
>*
H
^
r%
U
O
?
a
's
-H 9i
> *-l
U W
" S
JS -»
I 3
i a.
o *
2 a
4)
F-I t4
1 u
U U
Q O
c
41 S 41
3 « 3
u^u
1 '
X
a
^
5
fl
X
S ^
1 a
? ?
Soi
s»
a
0
^-t
a
H iM
M 4
4i a
U *H
. U U
(8 a
fl u
3 3
0
a u
o u
H a
u a
a u
u
4
A
«.
e
proxlmatlo
4 a
o 5
H ^
41
U
Xl-«
S 3
4
41 Z
1 1
41 4)
H »4
^a ^
fl5
41 41
41 41
tn tn
i i
u
o
5
1
fl
«
u
o
*w
|S
3 =
5 c
D
41
4
U
1
U
Qi
U
S
3
u
a
H
at
a*
1
1
w
a
41
41
3
a
jj
a
I
a
1
A
a i-
u o\
11
si
i i
u
i
O
«»^
O
at
u
5
M M
S5
<*
rt
A
W
3
H
*44
O
1
4
-H
1
rt
M
5
I
1
a
a
41
a
i
41
>
1
41
iH
H
41
CO
1
M
O
4-
fl
*H
-------
to occur in episodes, possibly 2 to 3 times per week (NAS, 1976). It
has been estimated that a child can consume somewhat greater than 1
gram within a 24-to 36-hour period, with cases reported of up to 20
grams within the same time period (Sachs, 1975) and that children
with pica for paint may consume 1 to 3 grams per week (NAS, 1976).
The low end of this range (1 g/wk) has been used in source contribu-
tion calculations as an estimate of paint intake in children with
pica.
Pulmonary and gastrointestinal absorption rates utilized in sub-
sequent calculations are also presented in Table 6-1. Most of these
figures represent average absorption values for inhaled or ingested
lead, as reported in the scientific literature. The absorption rate
estimated for lead in soil/dust was intermediate between the absorp-
tion rates for lead in food and paint, since no value was found in
the literature. Gastrointestinal absorption rates for children and
adults are provided.
6.2 Estimated Daily Lead Uptake from All Sources
The relative contribution from each route of exposure (i.e.,
air, food, drinking water, soil/dust, paint) to an individual's total
daily uptake has been determined from the specified environmental
lead occurrence data (Table 6-2) in the calculation sequence de-
scribed previously. Several concentrations of lead in drinking water
have been utilized, along with representative ranges of lead in air,
food, paint and soil/dust. Note that the values used represent
average levels resulting from continuous, chronic exposure and do not
reflect short term or episodic patterns of exposure (such as pica)
which may be toxicologically significant. Table 6-2 provides those
exposure values used in the calculations.
Dietary lead levels reflect daily lead intake excluding any con-
tribution by beverages. In the studies cited (FDA, 1975), beverage
intake for adults was less than half of the drinking water intake
83
-------
CN
1
VJ3
td
CP
<
S
ca
CO *
i-3 M
Cd CO
> S
Cd 4)
J as
Cd
DC!
3
O
ELi
X
Cd
Q
<
Cd
-4
J
H
Cd
Jg
O
as
M
Z
Cd
Ed
>
M
H
i
Cd
cn
Cd
OS
eu
as
CO
4)
3
O
as
4)
u
3
CO
o
Q.
^
Ed
a o *
4) O 04 X
60 M ' O
e u-i x u
M c T3 a.
o ^ ed
4( --4 60
»-4 VI "1 VI
J3 3 4)
e * m -a
0 U CN
CO vi 4)
eo e --4
4) O C cd
u u o s
.,4 4)
C vi vi 04
o ca 3
J3 -0 vl
O vl < .-4
4) U 3
CO CO VI -Q
(8 4> C es
.a -a o
3 0 -
eo -4 -Q
4) O 4) >-<
vi x 60-*
to 41 ta jr
S u o
1-1 4) <-N
vi co > -O to
CO 41 41 <-4 41
4) CJ .fi O **
e cd
41 60 S
vn n e M
1 4) -H X 04
I 03
.a e ao
co 4) cd X
fr4 4) V4 VI f«
3 4) -4 0)
4) vi > 3 vi
4) 4) 4) tj CO
W J3 -0 CO S
XXX
co co ca
"2*2*2
QO vO CO
O vO ON
o
41
O) CO 1*
S X
CO CU M
S 04 4
eg
O
a.
u
x
i^
M
4)
VI
M
ca
3
O*
*4
CQ
3
e
e
c9
M
CO
1 1
w
ca ca
4) CO
O T3
V4 ^*
0 1^
r-4
~-i
1 Z
CNCO
4) Z
J3 4)
CO 60
H cd
4) 4)
4) >
CO cd
1
en en
S H
60 60
ON ^^
ao i
O O
4)
60
CO
14
41 41
60 >
CO CO
U
CO
ca ja
^
e a
<0 1
j3 e
u a
3 Z
^
CO
T3
1
O
ON
o
c u
O *
VI 1-1
H -fl
r-4
cd X
3 U
tr ed
B
*^ w
ed a.
vi a
c *
4) lj
r4 41
A u
a c
<9 ^* -i-l
ao
-* c
OJ "4 CO
e 60 e
0 ed 0
4-1 0) VI
ca > ca
z 4 4/
ea aa
a
o
0 G ^
S co in
cd r>
03 ^^
4) 4) -4
co j:
O 4) X
A ta cu
^ c
60 CO
C eo S
f4 4)
vi 3 T3
co i-t C
*r4 01 C9
x >
41 ^ 4)
^^ 6 ^^
§r*^ Q) »-*
OS J3 O
M ""* %4 Qd
W C r-.
O C -^ oj o\
C *H 0Q _H
cd a ^
tO tU *-Q ^
vi i-s 3 ^j
o 4) ON u ca
CU "O »-4
ca 4) vi
O - - > 4)
a. B w <->
O ca <; vi 3
V4 4} Z CO O
a. s ^ -u a.
C 4)
VI *Q CO 4) n4
C 4) X CO
4) 5 4) 41
U 3 > U LO
ij to 14 a.r»
3 « 3 4J ON
f_^ ^^ CQ OS ^
| |
60 60 60 60
60 60 60 60
O O O O
O O vO O
v^» <*"< i^^
M «
ca i
-*
^*» ^-N
^ c
CO CO
Vl °
3 lJ
I- 3
^^^ ^^
VI
to
3
a
VI .
c -*
r4 >p4
CO O
Oi V3
-------
assumed in our calculations (0.9 and 2.0 I/day, respectively). The
exclusion of beverage intake from the FDA estimates eliminated any
double counting, since drinking water was entered in the calculations
as a separate category. In addition, the lead concentrations in
those beverages surveyed by the FDA were somewhat lower than the
range of lead levels in water that were subsequently utilized, so any
errors imparted by these manipulations would be toward conservatism.
Table 6-3 provides an example of the actual calculation sequence
employed. The source contribution factors calculated for air, food
and drinking water for the average adult male, based on the assumed
sets of exposure conditions, are presented in Table 6-4. The factors
for a pregnant female follow in Table 6-5.
Using the model for the lowest hypothetical urban exposure con-
dition (lead in drinking water at 10 M-g/1), representative intakes of
248 and 205 |j.g/day are indicated for the male and pregnant female,
respectively. These values are in agreement with measured values
(NAS, 1972; Goyer and Mushak, 1977; Tepper and Levin, 1975; Thompson,
1971; Goldberg, 1975). The source contribution factors for the aver-
age three-year-old child without pica and for the child with pica are
given in Tables 6-6 and 6-7. The model indicates that urban exposure
levels are much higher than .has been reported by most studies. Those
studies describing exposure conditions generally fail to include
soil/dust levels, or underestimate the high concentrations of lead
currently found in this exposure source (see Section 2.4). It should
be noted that these tables represent presumed average values, and do
not account for instances in which a particular environmental source
is high. For example, ambient air lead concentrations averaged Q.89
(jLg/rn-^ in 1974 (see Table 2-1), but the maximum reported quarterly
composite was 4.09 ^ig/nr. Obviously, in those instances the
percent contribution from each source will shift to reflect these
excursions.
85
-------
I
CO
in
rv -a-
in
en co
i-t
en
1
w
I
a. a
a i-i
< z
aa
a
at
a
ao
m CM
en
§r
a.
O
O
en
§
o
ao
a.
ao
a.
o
J3
W
g
d
O O
* vn
d d
o
o
en
vi
Cd
I
X
o
z
o
X
A
a
a
r>-
3
X
ea
ao
3.
S
s
E-i
2
u
1
o
en X
S en
H -«.. "Q
«. 00 -«,
00 3. 00
a a.
m
O en
m I-H CT\
ao
ao
O
o
o
a
u
as
o
en
31
u
CD
ao
c
U)
3
T3
O *
O O
Sa co
at
a.
86
-------
s
X
fl
ao
3,
>*
i
*
*»
* 3
i ^*
*c ~»
SB
S
5 1
a
>
3
1
to
ad
M
<
*
V4
03
S
OS
3
u §
C JJ
4) 3
U -C
01 M
a. u
e
3
0)
g
u
in O >n P"* \o t^» co p* in
mm *n *n « *»> -» eM
!r» oo O ft h» co Q >n r*. oo o *n
X X >»
"1
>
4J
S^ s* ^ -^^
aooo-^ oooo-v. oooo-x
3.3,00 3.3.00 3.3.00
a. a. 3.
J m co ~ m co ~ m ao
o o o m o o
i-*t H
a* u
*« 41 -.4 V » «
o c « « -a c ,« B ti c fl a
c*^in w**^ ooirtp^
vor*-v^ COQ Q 00
"a
.3
00-^ -1 00-- 7 M M
*? 1 ^S 5 *" «
0003 ^ 0303m 0300
. o 0 0 ^1 O O
O «M -* ON O CM *n
oo oo ao
e u c u e u
4)
u
LI
O
cn
-.44) i* « -4 <»
T«OU a THOU o w o u o
-: u. a H
0 CO
«*.
ao
a.
§
4)
fl fl
0
H
j-
CO
f^
2
a
01
3.
**!
i-»
03
f-*
^
CO
*
QC
a.
CO
a
<
QS
evi
CO
S
X
fl
00
3.
CO
o
CM
CM
0'
rt
CO
o
X
*lfc
3.
eo
Q
(M
T3
£
r«
!n
O >A
-T r*
^
OB
3.
§
(M
00
e u
*4 4)
a ^
o
03
in
o m
0 03
00
3.
8
00
.* -U ^4
a fl fl
a ^
u§
c *>
U 3
U J3
4) U
O* W
C
1
2
S
41
>
.J
S
3
5
N -
-------
8
Ill
1 22
it ~rf
=L i DO
«* =
T I
ED DAIL
S
a
i-
9) h
Ml
^1 >n %o o *
a . .
| a ";
.
. oo '^
a. oo
a. a« *.
a oo
.
a. ao
.
a. oo
O ^ (S Qi-tu-l
00 00
Qbi C W
-M OO
O--4CM
U 0 -* 3 w
-H a M o
< ^. o H
a u
«3
-
a oo
4a
«fl
-.00
88
-------
t-* CM m
-t o <* in
100 irt
"5
« ^
a. aa
"?
00
00
o in
t
c u
o hi a
ao m
M5
m >,
00*--
3. CO
^en
^
* 0 O
en
8 S3
00
00
o o
00
ao m
-T
tn >i
a «
a 00
. en
-
£l£
en
0 0
en r-. -T
en ^3-
oo
a, oo
O O
o o
00
c w
» s32
oo m
evi o
x
00 -*
2. Ofl
m
. m
^
-4 Q O
S
en
40
T
0
^
^
en
§s
§
BO
C U
U * Q
4
«
00
av
Si^
S
M
04
1
M
3 §
S 06
3 3
31
U
3
3
g
M
_I
>
wl
i
3
H
H
C/3
Cd
J
|
OS
g
si
u 3
a* -u
«
o
I
4)
>
0)
U
u
3
U)
g
C u
3) 3
U ^
U i*
V u
o> ^
1
0)
4J
Q
^
OJ
_!
U
3
C/3
^ ^
f-4 ^ »n
00 00
u c ^* c ^
0) W «4 lU W -H 01
3w u 0 -4 t3 ^ 3 " u O ^» Q --4 3 u
E-I n
00 . 90
U c 1- ^ C U
fl
^. (0 "v. fJ
0013 40 'C
a."*- a, oo
ao a.
O* a. Q
°° en °
-4
00
c u
W -r4 0)
"^- 01 Jtf *4 FJ
3 ^ 3 C fl «
* g -r4 ft 3 4J
3 u. « a H
CM m
^ -o
00
3 U
""» J) -^ iJ ^»
a -* 3 3 TI -fl
u o -^ a -. 3 -»
< u. cfl a H
O r*
v \a
r-» in
-4 \O O
en
8 X 00
*-. ea »-
OO-Q 00
a. ^s» a.
en o
O 0H
w
»«" m
B -t 3
i- o -H a
< U. CO
so a
-t ^T f-i
V (S|
CM in oO
0 ^ *^
n
o oo
-T ea
-
g.
o
o
u
n co
3 "
H
89
-------
-------
?sg
-J U
4 0-
a
o
k-
<
X
ss
I = S
ui = - 4 £>*>«; a -, «, a - v £ - i
U -^M.Xbf« ^.w^WM -^.ujtu.- ~^^Jt^_ --, W J .
M *9 s s « « -o e = ^ % ^ c c « * ^ s c «« « -o e s j
o --oowi. o O-OB^ o o o U o -M a 3 i* o «< Q o * i> "
M< OO-* i^r» >* O -J O<
fa _
t
; e em"
3 -; a *
2 2S
-------
The range of calculated source contribution factors is quite
large, if one considers all the possible permutations of lead levels
specified for the various media. In adults, the source contribution
factor for drinking water varies from about 5 to 70 percent. In
children without pica, drinking water contributes between 2 and 74
percent of the daily lead uptake. For the child with pica for paint,
drinking water contributes between 1 and 37 percent, depending on the
concentration of lead in soil/dust and paint. In a child with pica
for paint, soil/dust can account for as much as 82 percent of the
daily lead uptake, while paint can contribute as much as 78 percent.
The contribution from air varies from about 2 to 41 percent for an
adult and is almost insignificant for a child. Ambient lead levels
in air can be significantly higher than the values presented in
Tables 6-4 through 6-7, so the assumed range in atmospheric concen-
trations is somewhat restricted. The contribution of food to an
individual's total daily lead uptake varies from 24 to 87 percent for
an adult, from 9 to 84 percent for a child without pica, and from 7
to 66 percent for a child with pica for paint. The total daily lead
uptake in children is always higher than that predicted for adults.
93
-------
7.0 LEAD-UPTAKE/BLOOD-LEAD RELATIONSHIPS
Blood lead is the most widely used indicator of recent lead
exposure. It is also regarded as a reasonable surrogate for the
biological response associated with lead absorption. Since this is
the value most often reported in the literature to represent the
extent of lead absorption, it is necessary to relate daily lead uptake
to blood-lead values in order to define the toxicological impact
associated with the different levels of lead uptake determined by the
source contribution model. Because children and fetuses have been
identified as sensitive populations, it is necessary to derive this
lead-uptake-to-blood-lead relationship for both children and pregnant
women.
7.1 Child Relationship
There are no comprehensive studies in the literature which re-
port a lead-uptake-to-blood-lead relationship for children. Although
there are studies for adults, these can not be used to define a
relationship for children due to the differences in exposure
conditions and metabolic differences. Therefore, it has been
necessary to derive a relationship from the combined data of a number
of studies.
Data from six epidemiological studies have been used to derive
a relationship between lead-uptake and blood-lead values for children.
These studies were selected because each specified an environmental
lead -level for most of the major sources of exposure, gave the levels
for different exposure conditions (i.e., high and low exposure levels)
and reported corresponding blood-lead levels for each exposure circum-
stance.
Table 7-1 provides the data from these six studies. Since not
all of Che studies had values for every environmental source, it was
necessary to assume values in such cases. Footnotes in the table
94
-------
03
C/3
W
H
I
CJ
w
Cd
e/J
a
a
O
a
Ed
§
3
ca
Z
Cd
§
Ed
z
[d
Ed
T3 .
01
14
o oc
a 3.
II --
at
o .
a_i as
en t)
f-t CTV
en -*
-H O
en CM
9.
H
CU
eo
u oc
O
00
3.
Ed
O
CO ^^
3 00
a ~^
~v. OC
a
en
>-> a
< "oo
H
1
rt 3 3.
m en
CN CM
OO vO
O m
O O
O O
o o
0 O
o
o
oo en
en d
z
Cd
T5 ea
O -O
O >.
t- 00
a -a
en en
en en
cu 01
o o
m m
O T3
en en
en en
ooensrenoo^^ r* -j1 CM en CM
....... j£ si A
inOrsCMOOOCM ^G VD vO
oo ao r-< en CM <-* CM
oo so oo
OOOOOOO en
en en en en en en en en tn en en en en
01
tn
O -T
ai r-
c
O
u to
o
01 -^
4 OO
00 r~
c s tn
eg -^ f-4
so
H «*
ui in oi
-a i^* u
o ^ 2!
j] ra
p-i at
Q fi
M 01
01 3
> u
-4 Q. r3
"DC
!A Cz <3
II O ^
o "5 -< '
.c -a a
a i-< 01
C3 *^ T"
CJ
Ej
CO
c
c
il
CQ
95
-------
O ^N
1) _4
*J 73
o at
Q. 3.
u ^
04
*-( 1 t
o o
CN CN
O O
-I i-4
.-4 r*
NO NO NO NO
m in *3*
u to
M "O
CU -^
ao ac
ii
ao
CB 3.
CO
i-t T3
CB ^-
LJ o£
o
ao
3,
o co oo NO
CN iH
NO
Z
J3
[^
cn .^
3 00
a -.
~» ao
^ 3.
O
cn
«4-t
S oo t^ co
O ^O 10 r^>
O ^ r** &
O
O co
O T3
o --
&u oC
o.
-) ^1
^^ (^
CTN
01 I
01
^4 *
01
00 r-l
T3 03
E ^^
CO ON
14
01
r^
oo oi
c
rs H^
o
tic means.
01
g
~
>?4
^4
CO
01
u
C3
S
5
t
4.J
aj
u
C
11
u
r"
O
CJ
f^
r;
i
d interior dust values (unless otherwise noted
B
CO
n
U
01
3
-o
^4
a
H
t4
01
X
01
^
^
o
01
0)
00
CO
0)
>
j2
trations (exterior paint not considered).
B
01
CJ
E
O
O
jj
C
H
ffl
O.
u
o
o
-a
E
f4
01
.j
2
01
ai
cu
^i
c.
£
u
X
00
3.
c
0
H
taj
01
01
00
c
,.Q
JJ^
a
01
js
Oj
Jl
!**"
U
01
H
,4
^^
00
3.
O
m
II
u
oj
1 1
C3
3
E
H
.a
-*? ,
~?
S
2
cn
m
GJ l
interior dust concentration.
*^
B
CO
E
O
H
4_l
o
t_l
4_(
B
CU
a
B
o
o
r-4
r4
O
0)
0)
50
C3
01
>
±*
r^
r^.
ON
P t
M
E
O
4-1
01
01
u
OH
S
O
r^!
oo"
.
0)
~J
rH
fl]
J^
4J
CO
tJ
i^
o
0
o
c
wt
01
oo
CO
u
01
^
CO
tn
c
QJ
Jl
U
C.
0)
.
^*t
01
X
01
>
M
3
0]
u
CU
^
u
CO
S
T3
B
CO
4)
cn
3
O
Si
00
B
H
u
01
H
X
01
E
O
a
01
01
co
-0
S
a.
a.
o
o
o
00
II
01
J-l
'O
S
H
u
01
01
4-t
E
«H
CO
_-
"so
H
zration!
B
01
u
B
0
CJ
a
CU
JJ
B
01
u
)-.
CU
o.
NO
0
o
NU
o
o
u
CO
T3
S
CB
u
01
3
01
E
01
01
o
0.
o
0.
>l^
e
0.
0.
o
o
^o
II
OJ
u
«3
S
M
4J
CO
OJ
u
c
1-4
ca
"**
3
C
OO
r*-
3\
r-*
-------
describe the values used. In determining the total lead absorbed, the
absorption factors associated with the three-year-old, 15-kg child
were used. These factors have been previously identified in Sections
3.0 and 6.0. Figure 7-1 shows the straight-line relationship (y *
O.SOx + 7.85; r * 0.73) derived using data points based on these
studies.
The relationship based on total uptake (Figure 7-1) appears to
predict blood-lead values which agree with other reported values. For
example, at the specified urban background levels for the child
without pica (385.2 pig uptake/day; see Table 6-6), this relationship
predicts a blood-lead level of 28.4 )ag/dl. Other studies (Adebono-
jo, 1974; Joselow et al., 1975) place the estimate in the range of 28
to 30 p.g/dl.
7.1.1 Comparison with Other Relationships
Since data from other studies relating absorbed lead to blood
lead do so on the basis of ingested lead only, it was necessary to
derive another relationship based on that portion of the daily uptake
associated with ingested lead only. To do this, that portion of the
total daily uptake which was derived from the contribution by air was
subtracted, and the remainder (total uptake via ingestion) was equated
with the reported blood-lead levels. The amount to be subtracted was
determined by using the source contribution factors identified in
Tables 6-1 and 6-2. The values for lead uptake via ingestion only
were also provided in Table 7-1.
Several studies have described an ingested lead-to-blood-lead re-
lationship for children. Two relationships which will be considered
for comparison are those proposed by the National Academy of Sciences
(1972) and by Moore et al. (1977).
Clinical studies involving adult volunteers have determined that
the supplemental ingestion of 1 mg/day of lead as lead acetate or
lead chloride produces a 17 ^g/dl rise in blood-lead level over a
period of several months (Kehoe, 1961). If one assumes a gastroin-
testinal absorption rate of 10 percent in adults, then the 1 rag/day
97
-------
00
u
-a
(U
CO
e
o
1-1
O
H
CB
60
H
>-l
a
c
ON
00
B
O
u
c c
^ -s
c to
^?
in
o
o
en
a
Q.
X
0)
z
o
01
QC
o
<
111
Ed /-N Q
a|| gs
= " ^"S
11 ggu-
sj~ I9f
^2
tu
OQ
3 §
V)
OQ
<
>
O d
-1 <
a
o
1-
O
tn
O
cvj
(IP/3rt)
aooia
98
-------
intake rate corresponds to an uptake rate of 100 |u.g of lead per day.
For the average (70 kg) adult, the lead absorbed daily to produce the
17 ng/dl rise in blood-lead levels would be about 1.43 ng Pb/kg/day.
NAS (1976) assumed in developing their relationship that an increase
in lead uptake of 1.43 yg/kg/day in children will also produce a 17
|ig/dl rise in blood lead. Barltrop and Killala (1967) found that a
group of two-to-three-year old children with a mean blood-lead level
of 20 (ig/dl excreted an average of 67.8 [ig Pb/day/ person in the
feces. Assuming that this fecal lead was the 50 percent of ingested
lead that was not absorbed by the gastrointestinal tract, the daily
uptake of ingested lead by the average (15 kg) child would be 4.5
Hg/kg/day. The slope obtained from Kehoe (1961) data and these aver-
age lead uptake and blood-lead values were used by the NAS (1976) to
specify a lead uptake-to-blood-lead relationship. It should be
pointed out that the relationship considers only ingested lead and
does not differentiate between lead in drinking water and lead in
food.
The relationship proposed by Moore et al. (1977) is based on
a study involving neonates (10 days postpartum) to determine if any
association existed-between blood-lead levels and mental retardation.
This study was carried out in Scotland, where drinking water-lead
levels were in excess of 100 ng/1. In this study, blood-lead levels
were compared to water-lead concentrations in the maternal home during
pregnancy (Moore et al., 1977). No attempt was made to account for
other sources of lead exposure (i.e., air, soil/dust, paint), or to
determine the actual quantities of lead in the drinking water inges-
ted. This study does, however, provide an indication of the long-term
impact of high lead levels in water on blood-lead levels of the indig-
enous population.
99
-------
Figure 7-2 illustrates how these relationships compare with the
relationship developed from the six epidemiological studies on the
basis of ingested lead only. It was assumed that the blood-lead
values reported in the NAS (1976) and Moore et al. (1977) studies
were actual measured values. Since these values represent the
contributions from both ingested and inhaled lead, the reported
blood-lead values from the six epidemiological studies were used in
deriving MITRE"s ingested lead-only line. As can be seen in the
figure, the slopes of the lines are different and the choice of curve
will have a substantial effect on the value predicted for blood-lead
concentration.
The relationship developed from the six studies (uptake via
ingestion only) appears to agree well with the relationship derived
from the Moore et al. (1977) study. However, since the data of the
latter were obtained from ten-day-old infants, it is not certain how
representative these data are, since the mother's blood-lead concen-
tration (as previously described) will have a major influence on the
child's blood-lead concentration at this early stage of life.
The NAS relationship predicts a much greater increase in blood-
lead values than either of the other two relationships, with incre-
mental increases in the amount of lead absorbed. This difference
may be partially explained by the fact that the relationship was
developed by extrapolating adult data to conform with the intake
and absorption characteristics of a three-year-old child, thereby
ignoring any other metabolic differences between adults and children.
7.1.2 Major Assumptions
Several assumptions are necessary when using this relationship.
It is assumed that the relationship is approximately linear over a
specific range of absorption values (about 4 to 50 (j-g/kg/day) and
blood-lead values (i.e., 12 to 40 ng/dl). Other studies (Moore et
al., 1977; Berlin et al., 1977; Goldberg, 1974) have suggested that
the relationship may not be linear. It is further assumed that daily
100
-------
\ I
03
""> < T3
tM M >>.
> 80
ao
-------
intake values, as well as absorption rates for several environmental
sources (i.e., food, soil/dust, paint) were fairly constant in the
populations studied and approximated those used here. There are
studies which indicate that these values are highly variable (King,
1971; Lin-Fu, 1972; Mahaffey, 1977; NAS, 1976; Roberts et al., 1974).
The relationship was developed using data from six different
studies and applying the best available values concerning average
intake and absorption rates. In addition, the data used to derive
the relationship were specific to children. A.S has been pointed out
previously, it is necessary to use data obtained from children due to
exposure and metabolic differences. Extrapolation of adult data leads
to inaccurate predictions.
7.2 Adult Relationship
The fetus has been identified as sensitive to lead. There is a
close association between fetal and maternal blood-lead levels.
Therefore, it is necessary to discuss the relationship between
absorbed lead and blood lead for women. Although no studies were
found which reported data relating absorbed lead to blood lead in
pregnant women, several general statements concerning this
relationship in adults can be found in the literature.
Clinical studies suggest a blood-lead rise of 1.7 |j.g/dl for ev-
ery 100 }ig of ingested lead (Kehoe, 1961). Data reviewed by Barltrop
(1977) lead to the conclusion that blood-lead levels are increased by
approximately 2 p.g/dl for each 100 |o.g of ingested lead. Several
investigators have correlated increases in water-lead concentrations
with rises in blood-lead levels. These data have been compiled and
presented by Berlin et al. (1977). Table 7-2 summarizes these data.
These results were obtained for water concentrations around 100
H-g/1. The mean from these values is a rise of approximately a 2.5
^.g/dl in blood lead for every 100 HS/^ increase in water-lead
concentration.
102
-------
TABLE 7-2
RISE IN BLOOD LEAD LEVEL ASSOCIATED WITH
INCREASE OF 100 ug/1 IN WATER LEAD CONCENTRATION
RISE IN BLOOD LEAD WATER LEAD
(Ug/dl) SAMPLING PROTOCOL
1.3 Running Sample
1.2 First Flush
3.4 Running Sample
3.3 First Flush
1.8
2.0 - Running Sample
6.0 Running Sample
3.9 First Flush
0.83
1.9 First Flush
5.3 Full Flush
0.72 First Flush
1.3 First Flush
SOURCE: Adapted from Berlin et al., 1977.
103
-------
An additional study (EPA, 1977) suggested a range for the*
absorbed-lead-to-blood-lead relationship. This range was based on
data from studies involving lead absorbed from food and water in adult
populations. From these studies, it was estimated that for every 100
|j.g of ingested lead, a 6 to 18 |j.g/dl rise in blood lead would be
expected. However, it is apparent that a relationship which assumes a
rise in blood lead of approximately 2 (o.g/dl for every 100 ^ig of inges-
ted lead more closely approximates the majority of values reported in
the literature. Therefore, this relationship will be considered
representative.
Mean blood-lead levels and corresponding estimated uptake values
(through the source contribution model) were used as starting points
for deriving a line to depict the adult absorbed-lead-to-blood-lead
relationship. Reported values for average blood-lead levels in adults
vary according to sex: female levels are lower than those of males.
Three studies were used to define average blood-lead values for urban
women. The three reported values were 13.8 f-Lg/dl (based on 100 women
[Goldsmith, 1974]), 13.8 ng/dl (based on 52 women [Johnson et al.,
1975]), and 19.0 jig/dl (based on more than 400 women [Tepper and
Levin, 1975]). An average of these values, about 15 (ig/dl, was chosen
as the representative blood-lead level for an urban woman.
Representative urban environmental lead levels were used to
define the intake one would expect for an urban female. Using these
levels (i.e., air @ 1.5 (j-g/m^, food @ 166 |j.g/day, and water @ 10
(ig/1), an intake of 200 p.g would be expected. This level is well
within the range reported by a number of authors (NAS, 1972; Goyer and
Mushak, 1977; Tepper and Levin, 1975; Thompson, 1971; Goldberg, 1975;
Mahaffey, 1977) and is considered representative.
Using the absorption values for adults, this intake would cor-
respond to an uptake of 31.47 (ig Pb/day. Thus, a blood-lead level of
104
-------
15 |JLg/dl would be expected to result from an uptake of 31.47 jag Pb/
day. Converting this to the ug/kg/day scale, assuming a body weight
of 60 kg, would produce an uptake value of 0.524 ^ig/kg/day. Figure
7-3 shows the relationship derived when using these values. The line
(y = 14.Ix + 7.67) passes through the point defined as the mean urban
blood-lead level/mean urban absorption level, and has a slope based on
the relationship of a 2 |j.g/dl rise in blood lead for every 100 p.g of
ingested lead.
The ratio of 2 \ig/dl rise in blood lead for every 100 |j.g of
ingested lead was developed from data which reported a blood-lead
range of up to about 30 to 35 [xg/dl. For this reason, the relation-
ship is believed to be approximately linear up to this level. In at
least one study of blood-lead levels associated with high drinking-
water-lead levels (Goldberg, 1975), it was suggested that a
curvilinear relationship may be more representative at even lower
blood-lead levels. However, until further data are produced, it will
be assumed that the linear relationship is adequate for the ranges
reported here.
This relationship can be used to predict blood-lead levels for
the female, pregnant female, and adult male since the scale allows for
differing body weights. In addition, this relationship appears valid
for the pulmonary intake route. EPA (1977) reports a ratio of rise in
blood-lead levels to increase in ambient air lead concentrations of 2
p.g/dl blood lead per 1 p.g/m^ air lead. Assuming an increase in air
lead concentration of 1 ug/nH, an average adult male would inhale
22.8 |j.g Pb/day, while an average adult female would inhale 21.1
(jig/day. At a pulmonary absorption rate of 40 percent, the increase
in uptake for the male would be 9.12 fj.g/day and the for the female,
8.44 ng/day. These increases in uptake correspond to increases in
blood-lead levels of 1.8 (ig/dl in the male and 1.7 fig/dl in the
female. This compares favorably with the EPA prediction of a
2 |o.g/dl blood-lead increase for an increase of 1 H-g/m3 in air lead.
105
-------
25
20
1.5
o
a.
10
Y - 14.Ix + 7.67
J I
J I I I
0.1 0.2 0.3 0.4 0.5 0.6 .0.7 0.8 0.9 1.0
TOTAL LEAD UPTAKE (ADULTS)
(ug/kg/day)
1.1 1.2
FIGURE 7-3
TOTAL DAILY ABSORBED LEAD TO BLOOD-LEAD
RELATIONSHIP FOR THE FEMALE ADULT
106
-------
Thus, using this relationship, one can determine the estimated
rise in blood lead which would be expected in an adult following an
increase in the amount of lead absorbed from any environmental source,
including drinking water.
7.3 Comparison of the Relationships
None of the epidemiological or clinical studies reviewed by MITRE
has unequivocally characterized the physiological basis or
mathematical form of the lead-uptake-to-blood-lead relationship in
either children or adults. Although many of these studies have con-
cluded that the relationships are adequately represented by linear
functions, a number of authors have suggested that the relationships
are nonlinear.
The straight-line, lead-uptake-to-blood-lead relationships
utilized by Metrek are based on data reporting lead intake levels and
corresponding blood-lead levels and are presumed to have no more phys-
iological significance than that which is evidenced by their confor-
mity to these data. Linear functions were selected because: (1) they
appeared to adequately approximate experimental results (2) there was
no overwhelming evidence to suggest that the relationship is nonlinear
and no clearcut characterization of the form of such a relationship;
and (3) they were simple to derive and manipulate. Since the
equations have limited physiological significance, there is little or
no justification for using them to extrapolate blood-lead values
associated with uptake levels that are very far beyond the range of
the available data or beyond the normal uptake ranges defined by the
source contribution model (approximately 3 to 50 jj.g/kg/day for
children and 0.3 to 1.2 |j.g/kg/day for adults).
The relationships developed by MITRE predict that an incremental
increase in lead uptake will produce a greater increase in blood lead
in a pregnant woman than in a young child. However, since the two
107
-------
relationships are presumed to be valid only within specific,
nonoverlapping uptake ranges this observation does not necessarily
signify physiological differences, other than in uptake rates, between
children and pregnant females. A single nonlinear function could
conceivably describe the actual lead-uptake-to-blood-lead relationship
for both populations and would produce the observed results. However,
it is likely that physiological differences are at least partially
responsible for the observed difference in the slope of the relation-
ships. Children may more readily accept lead into their relatively
empty dense bone pool than adults, and thus retain a smaller fraction
in the blood and tissues which exchange rapidly with it. Even if
there were actual physiological differences resulting in two,
more-or-less similar curves, these differences would not be apparent
from the available data. The regions of the curves in closest
proximity to each other represent extremely high lead intake levels
for adults and extremely low intake levels for children; therefore,
corresponding portions of the two curves would never be manifested in
a single population.
108
-------
8.0 WATER-LEAD/BLOOD-LEAD SCENARIOS
To evaluate the adequacy of the interim primary drinking water
standard for lead, it is necessary to predict the blood-lead levels
associated with various concentrations of lead in drinking water for
identified sensitive populations, and to determine the extent to which
altering the maximum allowable concentration of lead in drinking water
may affect these populations (via the toxicological consequences
associated with changes in blood-lead levels).
By combining the derived lead-uptake-to-blood-lead relationship
with the percent contribution values from the source contribution
model, the relationship between varied water-lead exposure and
resultant blood-lead values can be drawn. In the source contribution
model, any specific subunit of the total population is defined by
representing the characteristic exposure concentrations and
physiologic parameters associated with that subunit. Furthermore, the
considerable variation from predicted average exposure levels seen in
some subunits of the population, particularly children, and in certain
regional or local situations (e.g., close proximity to smelting
operations), can be accommodated by the model, since any set of
environmental conditions can be utilized.
»
8.1 Water-Lead-to-Blood-Lead Relationship in Children
Separate water-lead-to-blood-lead relationships have been defined
for the following specific subunits of the child population: rural
children without pica, rural children with pica for paint who are
exposed to paint containing lead at the current standard, rural
children with pica exposed to paint containing lead at levels above
the standard, and urban children in the same three categories (Figure
8-1). The assumed exposure conditions are given on the figure; the
109
-------
50
40
30
10
ASSUMED EXPOSURE CONDITIONS
Rural Curves
Urban Curves
Air (ug/m3)
Food (ug/day)
Dust/Dirt (wg/g)
Paint (ug/g)
Water
I
1
0.11
93
60
2
3
0.11
93
60
0.11
93
60
600 8000
Given on Abscissa
I
2 _ 3
1.5 1.5 1.5
93 9.1 93
11.000 11,000 11,000
600 8,000
Given on Abscissa
I
0 10 25
50 100 150
LEAD CONCENTRATION IN DRINKING-WATER (ug/1)
200
Air at ambient standard.
Blood-lead levels calculated from total uptake, based on exposure conditions shown.
FIGURE 8-1
EFFECTS OF VARYING LEAD CONCENTRATIONS IN
DRINKING WATER ON THE BLOOD-LEAD LEVELS
OF A HYPOTHETICAL 2 YEAH OLD CHILD
110
-------
lead concentrations in drinking water is given on the abscissa. The
six resultant relationships allow comparison of the effect on blood
lead of increasing water-lead concentrations in urban and rural
children.
The relationships between water-lead exposure and blood-lead
levels (Figure 8-1) share a common slope since each reflects the same
rate of change in total uptake. Therefore, each shows the same
constant increase in blood lead over the range of water lead
considered. The total blood-lead increase over the range of 10 to 200
Hg/1 lead in water is 6.7 pig/dl, represented as a slope of 0.035 in
each of the lines in Figure 8-1. The y-intercept of each line has
been determined by calculating the total lead uptake from all sources
except water and then calculating the expected blood lead at this
uptake.
Analysis of the effect of varied water-lead intakes in reference
to the critical threshold level of 30 (J-g/dl, chosen by EPA and CDC,
reveals urban children as the sensitive subgroup. Although water may
comprise as much as 42 percent of the source contribution in rural
children exposed to lead in drinking water at the current standard,
their total blood lead (12.3 ^.g/dl) is well below the critical
threshold level (see Table 8-1). Urban children without pica, at the
current drinking water standard and above, have blood-lead values near
the critical threshold level. Urban children with pica for paint
(with lead-containing paint at the current standard) have blood-lead
levels of 30 fig/dl at water-lead levels below the current standard
(50 |j.g/l), and blood-lead values well above the critical threshold
level at water-lead levels above the standard. Urban children with
pica (with lead-containing paint above- the standard) display
blood-lead levels well above the critical level at water-lead levels
below the current standard (Table 8-2).
Ill
-------
^
1
CO
w
H]
3
s
3
M
ft.
a
0
ss
H
3
Z
H
ESS
3
a
u
Z
g
rJ
O
Q
«
Q
£?
<,
M
2
H
Pu
1
13
-------
CM
I
CO
W
5
fr*
H
Z
M
ft.
ft-
2
u
M
PL.
S
M
3
Z
id
Q
!
s
Z
M
a
u
i-4
a
§
P3
O
z
"^
W
r^
^J
&
a
Cd
»**
r-3
t^
^C
o
Q
W
&"!
^c
2
£
C/5
sj
H
M
^
e^
»2j
W
M
§
^q
1
3
el
3
at
a
"O ^*
O cC
o ^
«~
«
r-l Of
1H 3.
et) "**
Q
I-l ^
eg ed
u u
o a
EH 3
"S
(U /-.
a
o oc
O 3.
a
£j
rH 01
Tf 3.
Q^
iH ^
cd ^
4J 4J
£ &
13
Jr7
T3
O 00
O ^
O3
K
^s*^
r-l &C
i-l 3.
cct '
a
r-l ^
cd ea
U 4-1
o a.
H 3
H C
"2T eg
L^J*1
M
^
rH
en
en
rH
o
:O
rH
00
3.
O
O
rH
CN
CM
*
s^
en
vO
rH
CM
*
n
CM
^
vO
in
3-
CM
CO
CM
rH
en
0
0
o
CO
en
vO
en
cn
en
en
in
en
v<3
en
CO
CM
en
f*.
00
rH
rH
en
o
CM
O
O
rH
~~.
00
3.
O
o
CM
cn
in
sr
^o
en
r^
0>
m
-»
m
CM
rH
en
oo
CM
CO
CM
CO
cn
o
o
o
co
>
rH
H
S
rH
ed
O
U
O
to
C
3
u
3
IH
U
4J
0
u
-------
At the current water standard, water lead represents 8.5 and 8.2
percent of the total source contribution for urban children without
pica and urban children with pica for paint (lead-containing paint at
the standard), respectively. In children with pica, with lead-
containing paint above the standard (8000 jig/g), water lead provides
5.8 percent of the total daily lead uptake. Thus it is evident that
water contributes only a small amount to the blood-lead level of
children compared to other environmental exposures (i.e., soil/dust
and paint). In pica children (paint lead at 8000 H-g/g) lowering the
water-lead concentration from 50 to 10 \ig/l produces a decrease in the
percent contribution of water lead to total daily lead uptake from 5.8
to 1.2 percent.
The decrease of 1.4 (ag/dl blood lead, due to the lowering of
water lead from 50 to 10 p-g/1, is the same for each child subunit
relationship as it is determined solely by the slope of the lines. In
the rural low-intake situation (i.e., no pica), the drop of 1.4 fig/dl
is a result of a decrease in percent contribution of water from 41.9
to 12.6.
8.2 Water-Lead-to-Blood-Lead Relationship in Pregnant Women
The combined use of the derived lead-uptake-to-blood-lead
relationship and the source contribution model yield a water-lead-
to-blood-lead straight-line relationship. Variations of lead
concentrations in air are assumed to represent the rural-to-urban
environmental gradient; while lead levels in food are assumed to
remain relatively constant. Three air-lead concentrations were used
to define the rural-to-urban gradient reflected in the total daily
uptake value (Table 8-3). Using the derived uptake-to-blood-lead
relationship, the blood-lead levels at these total daily uptake rates
determined and were plotted against the varied water-lead
concentrations (Figure 8-2).
114
-------
en
I
00
W
j
9
61
Q
2
a
H
U)
06
<
H
Z
W
M
CQ
co 2
u -3
3
M
b.
H
S5
U4
OS
cu
M
1
Q US
8 i
»j a:
flQ 5
a
^
M
^
H
a*
'j
d
id
a) /-N
o~~
o oc
o ^
-K
r-4 'M
H 3.
cd "^
O
4)
i-4 Jtf
cd cd
4J 4J
o a
H EJ
cd
hJ rH
TJ
O OC
O J.
r~t >*
K
>^,^\
^-1 00
H A
cd >^
0)
cd ca
o a
H U
O r*^ ao -( -( ,
r-l
H
cd
a
a
H
C/3
tJ
J r-l
"O *«.
O 00
O J.
en
CN
o a.
CO
3.
00
2.
O
in
00
3.
00
3.
O Q
O Q
^ CN
m
c
o
o
u
0)
u
u
o
115
-------
%.
X V
en * 41
tO U
a «
>- u
ao *
3. -a
fi
>O -H
80
a.
CO
o
-a
OS
Ed
1
CO CM i-t
SO
3.
I
S S
o o>
a
z
o
i
ta
u
i
u
a)
a
o
o
o
u
o
a.
c
o
05r
cna
o5
iu m
OC
Q
116
-------
The three lines in Figure 8-2 illustrate the effect of increas-
ing water-lead concentrations on three separate subgroups of the
pregnant female population. It is apparent, as in Section 8.1, that
the three lines share a common slope; thus they depict the same con-
stant increase in blood lead over the exposure range of water lead.
The total increase in blood lead over the range of 10 to 200 ug/1
lead in water is 8.9 ug/dl, represented as a slope of 0.047. The
y-intercepts are determined from the total uptake values computed by
the source contribution model with water at zero, by their subsequent
input into the derived-uptake-to-blood-lead relationship.
Although the fetus population has been identified as a sensitive
group, urban pregnant women have blood lead values which vary only by
2.7 fig/dl (at the ambient air standard) from blood-lead values of
pregnant rural women. The blood-lead level of these urban women at
the current water standard is 16.8 |j.g/dl, well below the 30 ng/dl
level set on by EPA and CDC as the level of undue lead absorption.
As presented in Table 8-3, the percent contribution of water
to total lead uptake in pregnant urban women ranges from 6.4 percent
(at 10 M-g/D to 25.5 percent at the standard (50 (j.g/1). Despite this
percent contribution difference, the effect on blood lead of lowering
the water-lead level from 50 to 10 jj.g/1 is a decrease of only 1.8
(j.g/dl, a small fraction of the total blood lead.
8.3 Blood-Lead Contributions from Individual Sources
The straight-line relationships defined in this report between
lead uptake and blood lead do not predict the expected blood-lead
value of zero at a lead uptake of zero for either of the two sensitive
populations considered. Perhaps this reflects significant deviations
from linearity at low uptake values and the inability to accurately
quantify all lead sources, especially at low levels. An implication
of the nonzero intercepts is that an increase in lead uptake does not
117
-------
produce a proportionate increase in blood lead; for example, in the
case of the urban pregnant woman (Table 8-2), with an.air-lead
concentration at the proposed standard, an increase in total daily
uptake from 31.3 to 49.3 ug (58 percent) produces an increase in blood
lead from 15 to 19.2 p.g/d.1 (only 28 percent).
Assuming that subsequent to absorption lead taken up from the
various environmental sources is indistinguishable to any physio-
logical process it is possible to determine the blood-lead level
attributable to any one source. This assumption implies that the
percent contribution of a source to total lead uptake is equivalent to
its percent contribution to blood lead. Source contribution factors
can then be used to determine blood-lead levels resulting from
individual sources. These source contribution factors are shown in
Tables 8-1 through 8-3.
From data presented in these tables, it can be inferred that a
constant uptake level from any one source does not contribute a
constant amount of blood lead. Rather, a constant uptake may be
responsible for different amounts of blood lead at different total
uptake levels (as well as different percentages of the total blood
lead). This effect is related to the nonzero y-intercepts of the
lead-uptake-to-blood-lead relationships. In the pregnant female, with
air lead at the proposed standard, there is a 58 percent increase in
total lead uptake as lead in drinking water rises from 10 to 100 H£/l.
A proportional increase in blood lead would lead to a value of 23.7
|j.g/dl; however, the defined relationship predicts a blood-lead level
of 19.-2 |j.g/dl, which is about 19 percent lower. Since uptake from the
individual sources is indistinguishable, the blood lead attribut-
able to each source will be 19 percent lower than that expected on the
basis of proportional increase in uptake. For example, the uptakes
from food and air remain constant (a proportional increase of 0
percent); therefore, the blood lead associated with these sources will
118
-------
decrease by about 19 percent. Uptake from drinking water increases
from 2 to 20 (J.g/dl (900 percent) ; a proportional increase in blood
lead due to drinking water would give a value of 9.6 ^.g/dl, and a 19
percent reduction in this value would give an actual blood-lead level
due to water of 7.8 (ig/dl.
119
-------
9.0 CONCLUSION
The toxic effect of lead absorption is the cumulative result of
exposure from many different sources. In order to define the toxico-
logical impact associated with specific environmental lead-source
concentrations, it is necessary to jointly consider all of the major
exposure sources.
There are appreciable differences in exposure conditions between
specific subsets of the population (e.g., adults vs. children, child-
ren with pica vs. children without pica, rural vs. urban populations)
and these can be characterized by average exposure assumptions for the
subpopulations in question. However, there is variability in the
specific exposure conditions of individuals within these
subpopulations which cannot be adequately quantified. The lead
exposure of children with pica for paint is a striking example of this
problem. Because of the wide variation in the lead concentrations in
paint and existing painted surfaces, and the presumed wide range in
rates of paint ingestion by children suffering from pica, the use of
estimates of average paint-lead concentrations and consumption rates
cannot reflect the diversity of blood-lead levels seen in these
children.
This variability in exposure levels implies that there is con-
siderable variability in the source contribution factors for all of
the major environmental lead exposure sources. The significance of
varying the maximum allowable concentration of lead in any medium,
measured in terms of the ability to thereby modify the blood-lead
levels of the population (or one or more sensitive populations), is a
function of the total daily lead uptake, and the source contribution
factor for that medium. Therefore, the effect of a standard for that
medium will not be uniform; rather, it will differ greatly between
individuals.
120
-------
9.1 Approach
If all sources of environmental lead are considered, the most
effective means of reducing the overall blood-lead value of a given
population can be determined. Utilization of the source contribution
model provides the necessary data, since the percent contributions
from various environmental sources and the total lead uptake at
different environmental levels have been outlined. The model shows
which environmental sources are most responsible for the given
blood-lead level and thus identifies those areas in which regulatory
action will have the greatest impact on blood-lead levels.
Large subsets of the population have been identified as being at
a considerably higher risk from lead than the population as a whole.
Therefore, it seems logical to approach the drinking-water lead
standard from a sensitive population perspective. The standard can
then be designed to directly benefit either or both of the sensitive
populations, or a more sensitive subgroup (e.g., urban children, urban
children with pica). Each of these options must be identified and
discussed in terms of its impact on the final standard.
9.2 Effects of the Standard
The intent of any reduction in a standard for lead should be to
lower the blood-lead levels of the exposed population, and in particu-
lar to reduce the blood-lead levels of those subgroups of the general
population who have a greater risk of lead exposure (children) or who
are more sensitive to lead than the rest of the population (fetuses
and children). Since the American Pediatrics Association and the
Center for Disease Control (CDC) have suggested that 30 p.g Pb/dl blood
is that threshold above which clinically significant adverse effects
are noted in exposed children, it is prudent to assess the adequacy of
the current standard in terms of the number of individuals whose blood
lead falls above 30 |ig/dl.
121
-------
According to our results, lead-contaminated drinking water gene-
rally contributes a small fraction of the total daily lead uptake, and
therefore will have only limited impact on blood lead. For example, a
reduction of drinking water lead from 50 (ig/1 to 10 (j.g/1 is expected
to lower the mean blood lead of the hypothetical child population by
about 1.5 |J.g/dl, or a pregnant female population's mean blood lead by
1.8 fig/dl. For high-risk youngsters (e.g., urban, inner city children
with pica) with blood-lead levels approaching 35 or 40 fj^/dl, the
utility of a regulation that reduces blood lead by 1.5 |JLg/dl might be
questioned. However, for the population as a whole, a reduction of
1.5 (J.g/dl in the mean blood-lead level can be substantial.
Blood-lead levels of U.S. children have been characterized as
log-normally distributed, with a geometric.standard deviation (GSD) of
between 1.3 and 1.5 (EPA, 1978b). Given the 30 (ig/dl threshold level,
one can identify the percent of the exposed population with blood-lead
levels below 30 fig/dl given a geometric mean blood-lead level. Or, if
a selected percentage of the population is to be protected (as a
safety margin), one can determine the particular geometric mean which
will insure that that percentage will not exceed 30 fig/dl. In effect,
this statistical treatment allows one to define the extent to which
the "tail" of the frequency distribution exceeds a particular blood-
lead level. A reduction in mean blood-lead levels of the childhood
population, regardless of how small in relation to an individual's
blood lead, can affect a significant portion of the total population
by displacing the frequency distribution. Thus fewer individuals will
exceed a defined threshold level (see Figure 9-1).
Using standard statistical methods applicable to log-normal
distributions, one can calculate the mean (geometric) blood-lead level
required if less than 99 percent of the observed population are to
122
-------
o
a.
Reduction in mean blood lead
Threshold level
x' x
In Blood lead (Hg/dl)
number of individuals with blood lead levels exceeding
the threshold, given geometric mean of x
number of individual with blood lead levels exceeding
the threshold, given geometric mean of x'
FIGURE 9-1
EFFECT OF A REDUCTION IN MEAN BLOOD LEAD LEVELS ON
THE NUMBER OF INDIVIDUALS EXCEEDING A THRESHOLD
BLOOD LEAD LEVEL: LOG NORMAL DISTRIBUTION
123
-------
have a blood-lead level less than 30 (ig/dl. Assuming a geometric
standard deviation of 1.4 (Angle and Mclntire, 1978), and utilizing
the following relationships:
(9-1)
In y - In M,
In Sg
g
z
and i rz i_.2 (9-2)
F(z) =
g e0.5 In* Sg
where y » the CDC limit of 30 (ig/dl
Mg the geometric mean
Sg =» the geometric standard deviation
z 3 a standardized random variable
F * fraction of the population with
blood lead less than 30
M " the arithmetic mean
one can determine what fraction of the exposed population would have a
blood-lead level less than 30 [xg/dl, given various population mean
blood-lead levels (see Figure 9-2).
Using the relationship in Figure 9-2, and the source contribu-
tion model discussed previously, one can determine the proportion of
the sensitive subpopulations with blood-lead levels below 30 fig/dl
as different control scenarios are applied to lead in drinking water.
Tables 9-1 and 9-2 indicate those percentages (people with blood-lead
less than 30 (j.g/dl) for the various subgroups of both identified
sensitive groups.
124
-------
99.99
o
en
V
3
I
O
O
O.
O
99.95
i
95
90
80
70
60
50
40
30
20
10
5
-------
to
en
z
o
M
H
3
J
PU
o
Ou
03
en
a
j
i_t
S3
O
en .
3
O
H-l
OS
^-4
<;
04
o
C*4
en
J
cd
>
u
J
o
5
Cd
. J
. 1
1 0
<* 0
M °
S >->
« «
MH
M a
H td
f-i
u
Cd
^"5
o
OS
04
=c
H
M
a
Cd
H
<
i i
CJ
0
en
en
4 ^^
O -9
JJ OC
to i
3 O
o»«n
o
04
ON -
a\ O\ CO G^ C^ OO
\f\ Srf» » I ^ ^ ___
ON ON OO ON ON 00
/\ /** s\ /\
J3
TJ
<*» -
-4 -H CN -^ -4 CM
V V V V
60 60 60 60
*eb~6b "M 50
H -< 3-3-
^ ZL "^
O O ° 2
oo oo
o o ^2
oo oo .
. _^
f^ ^^
«^_ SJ fpl ^^^ s^ f°l
6fl S^..,
i AJ AJ dL AJ u
c c 55"
0 -H -H 0 '^ '^
,« to to <-< to to
a. a 0" o.
s; to^ -^ 0 S 3
t, ^ i L^ «f^
tt) O-WtO 4> O4«tO
jj y y J-l O O
to o ** "* « o -r4 '.T1
3 ZOMO- 3 zo-O-i
^
0)
o
o
s
3
48
0)
l
|
a
o
o
1-4
,0
0
^J
0)
^
to
4J
a
3
"c
0
.^4
4J
3
A
'r*
|j
i t
^4
c
o
o
qj
U
M
o
CO
%
JZ
o
4J
U
o
4
T3
-------
TABLE 9-2
SAFETY FACTORS ASSOCIATED WITH PROJECTED
BLOOD-LEAD LEVELS FOR VARIOUS PREGNANT FEMALE SUBPOPULATIONSa
RURAL (Air @ 0.11 |ig/m3)
Mean Blood Leadb
Population Below
30 ng/dl (%)
Water @ 50 fig/1
Water @ 10 (ig/l
14.2 ng/dl
12.3
> 99
> 99
URBAN (Air @ 1.5 g/m3)
Water @ 50 jj.g/1
Water @ 10 jig/1
16.8
15.0
> 99
> 99
asg = 1.3
^Arithmetic means as predicted by the source contribution/uptake to
blood-lead model.
327
-------
More than 99 percent of rural children without pica, rural
children with pica at low paint lead levels, and all female adults
are expected to fall below the 30 ng/dl blood-lead guideline, given
drinking water lead at the current interim standard of 50 jj-g/dl.
Decreasing drinking water lead levels for these groups would have a
negligible impact, since most individuals within those groups are
already below the threshold. A larger proportion of the urban child
population exceeds that 30 p.g/dl blood-lead level; however, the drink-
ing water contribution is only a small fraction of their total daily
lead uptake. Assuming drinking water lead at 50 ug/1, between 43.2
and 88.6 percent of the urban child population is expected to have
blood lead in excess of 30 [ig/dl (see Table 9-1). By reducing the
lead content of drinking water to 10 (J.g/1, between 37.4 and 84.5
percent would exceed the 30 u.g/dl threshold.
The complete elimination of water lead from the uptake of the
urban child yields mean blood-lead levels of 28.1, 28.9 and 38.4
(jig/dl for children without pica, with pica at low paint-lead concen-
trations, and with pica at high paint-lead concentrations, respec-
tively. The corresponding percentages of the population falling below
30 (J-g/dl are 64.1, 61.0 and 17.0, respectively. Therefore the total
elimination of water lead in these groups adds 1.5 percent of the
population to that portion already below the 30 ng/dl guideline.
The reduction of water-lead concentration does not appear to
greatly affect the blood-lead distribution of the child population.
However, an additional 6 to 7 percent of the population over the 30
(jLg/dl guideline will now fall within the "protected zone."
The effect of reducing the water-lead standard upon the fetus
population is not clearly defined by the 30 ^g/dl threshold criterion.
It is apparent upon viewing Table 9-2 that water-lead reduction,
although lowering the mean blood-lead level somewhat, has a negligible
effect on. the proportion of the adult female population below the 30
level. The majority of the female adult population is at no
128
-------
no apparent hazard at the environmental concentrations considered.
These blood-lead values (Table 9-2) , although well below the threshold
level, result in similar blood-lead levels in the newborn.
Since the fetus and the newborn are at substantial risk, it may
be prudent to reduce the maternal blood-lead levels. For the adult
female population, any change in lead levels in drinking water will
have a proportionately large effect on blood-lead levels (due to the
large source contribution factor), even though those blood-lead levels
are already substantially below the 30 fig/dl threshold level.
129
-------
Research Needs
Additional research is needed in several areas in order to
properly evaluate the validity of the results obtained by using the
source contribution model:
Rates of intake of soil/dust and paint by children and the
rates of absorption of the lead in these sources have not
been adequately characterized.
There are only'limited data regarding host and environmental
factors that affect lead intake, uptake and toxicity (e.g.,
age, nutritional status, hormonal status, chemical form).
The toxicological differences between chronic and episodic
exposures have not been properly evaluated.
Comprehensive cost/risk/benefit analyses of all sources of
lead exposure must be undertaken in order to determine the
best overall regulatory approach.
130
-------
10.0 REFERENCES
Adebonojo, F.O., 1974. "Hematologic status of urban black children
in Philadelphia: emphasis on the frequency of anemia and elevated
blood lead levels." Clinical Pediatrics 13:874-888.
Akland, G.G., 1976. Air Quality for Metals, 1970-1974. from the
National Air Surveillance Networks. EPA-600/4-76-041. U.S. Environ-
mental Protection Agency, Washington, D.C.
Alexander, F.W., 1974. "The uptake of lead by children in differing
environments." Environmental Health Perspectives Experimental Issue
No. 7:155-160.
Alexander, F.W., H.T. Delves and B.E. Clayton, 1972. "The uptake and
excretion by children of lead and other contaminants." Int. Sympo-
sium of Environmental Health Aspects of Lead. Amsterdam.
American Lung Association, 1978. Press Release for "Clean Air Week,"
1-7 May 1978, dated 28 April 1978. New York, New York.
Angle, C.R. and M.S. Mclntire, 1978. "Airborne lead and children
the Omaha study." Archives of Environmental Health (in press).
Angle, C.R. and M.S. Mclntire, 1975. Lead; Environmental Sources
and Red Cell Toxicity in Urban Children. EPA PB-249-061. U.S.
Department of Commerce, National Technical Information Service
Report.
Atkins, P.R. and P. Krueger, 1968. The Natural Removal of Lead Pol-
lutants from a Suburban Atmosphere. Technical Report #98. Federal
Water Pollution Control Administration, Washington, D.C.
Baglan, R.J., A.B. Brill, A. Schulert, D. Wilson, K. Larsen, N. Dyer,
M. Mansour, W. Schaffner, L. Hoffman and J. Davies, 1974. "Utility
of placental tissue as an indicator of trace element exposure to
adult and fetus." Environmental Research 8:64-70.
Baloh, R.W., 1974, "Laboratory diagnosis of increased lead absorp-
tion." .Archives of Environmental Health 28:198-208.
Baltrop, D., 1966. "The prevalence of pica." American Journal of
the Diseases of Children 112:116-123.
Baltrop, D., 1977. "Health Hazards in Drinking Water": Medical
Aspects of Lead Hazard. WHO Working Party, London.
131
-------
Barltrop, D. and H.E. Khoo, 1975a. "Nutritional determinants of lead
absorption." Trace Substances in Environmental Health, Volume IX.
D.D. Hemphill (ed.). University of Missouri.
Baltrop, D. and H.E. Khoo, 1975b. "The influence of nutritional fac-
tors on lead absorption." Postgraduate Medical Journal 51:795-800.
Barltrop, D. and H.E. Khoo, 1976. "The influence of dietary minerals
and fat on the absorption of lead." The Science of the Total Environ-
ment 6:265-273.
Barltrop, D. and N.J.P. Killala, 1967. "Fecal excretion of lead by
children." Lancet 2:1017-1019.
Barry, P.S.I., 1975. "A comparison of concentrations of lead in
human tissues." British Journal of Industrial Medicine 32:119-139.
Barry, P.S.I, and D.B. Mossman, 1970. "Lead concentrations in human
tissues." British Journal of Industrial Medicine 27:339-351.
Bayley, M. and D.R. Brown, 1974. "Low renal lead excretion in lead-
treated immature rats." The Pharmacologist 1JK2);207.
Beattie, A.D., J.H. Dagg, A. Goldberg, I. Wang and J. Ronald, 1972.
"Lead poisoning in rural Scotland." British Medical Journal 2;cl88.
Berlin, A., R. Amavis and M. Langevin, 1977. "Research on lead in
drinking water in Europe." Working Group on Health Hazards from
Drinking Water, 26-30 September 1977. London, England.
Bethea, R.M. and N.J. Bethea, 1975. "Consequences of lead in the
ambient environment: an analysis." Residue Reviews 54:55-77.
Betts, P.R., R. Astley, D.N. Raine, 1973. "Lead intoxication in
children in Birmingham." British Medical Journal 16:402.
Billick, I.H. and V.E. Gray, 1978. Lead Based Paint Poisoning
Researeh; Review and Evaluation, 1971-1977. U.S. Department of
Housing and Urban Development, Office of Policy Development and
Research. U.S. Government Printing Office, Washington, D.C.
Bird, D., 1971. The New York Times, August 4, 1971, p. 18.
Blake, K.C.H., 1976. "Absorption of 2°3pb from gastrointestinal
tract of man." Environmental Research 11:1-4.
Blumberg, W.E., J. Eisinger, A.A. Lamola and D.M. Zuckerman, 1977.
"The hematofluorometer." Clinical Chemistry 23(2):270-274.
132
-------
Bogen, D.C., G.A. Welford and R.S. Morse, 1976. "General population
exposure of stable lead and 210pb to residents of New York City."
Health Physics 30(4);359-361.
Booker, D.V., A.C. Chamberlain, D. Newton and A.N.B. Stott, 1969.
"Uptake of radioactive lead following inhalation and injection."
British Journal of Radiology 42:457-466.
Boyland, E., C.E. Dukes, P.L. Grover and B.C.V. Mitchley, 1962. "The
induction of renal tumours by feeding lead acetate to rats." British
Journal of Cancer 16:283-288.
Bridbord, K., 1978. "Occupational lead exposure and women." Preven-
tative Medicine 7:311-321.
Brown, D.R., 1975. "Neonatal lead exposure in the rat: decreased
learning as a function of age and blood lead concentrations." Toxi-
cology and Applied Pharmacology 32:628-637.
Bruhn, J.C. and A.A. Franke, 1976. "Lead and cadmium in California
raw milk." Journal of Dairy Science 59(10);1711-1717.
de la Burde, B. and M.S. Choate, 1972. "Does asymptomatic lead expo-
sure in children have latent sequelae?" Journal of Pediatrics
^: 1088-1091.
de la Burde, B. and M.S. Choate, 1975. "Early asymptomatic lead
exposure and development at school age." Journal of Pediatrics
87_: 638-462.
Bureau of Water Hygiene, 1970a. Community Water Supply Study:
Pueblo County, Colorado. Public Health Service, U.S. Department of
Health, Education, and Welfare, Washington, D.C.
Bureau of Water Hygiene, 1970b. Community Water Supply Study:
Kansas City, Kansas-Missouri. Public Health Service, U.S. Department
of Health, Education, and Welfare, Washington, D.C.
Bureau of Water Hygiene, 1970c. Community Water Supply Study; San
Bernardino-Riverside-Ontario, California. Public Health Service,
U.S. Department of Health, Education, and Welfare, Washington, D.C.
Bureau of Water Hygiene, 1970d. Community Water Supply Study: New
York SMSA. Public Health Service, U.S. Department of Health, Educa-
tion, and Welfare, Washington, D.C.
133
-------
Butler, J.D. and S.D. MacMurdo, 1974. "Interior and exterior atmo-
spheric lead concentrations of a house situated near an urban motor-
way." International Journal of Environmental Studies 6:181-184.
Butt, E.U., R.E. Nusbaum, T.C. Gilmour and S.L. Didio, 1964. "Trace
metal levels in human serum and blood." Archives of Environmental
Health 8;52-57.
Byers, R.K. and E.E. Lord, 1943. "Late effects of lead poisoning on
mental development." American Journal of Diseases of Children 66;
471-494.
Campbell, B.C., A.D. Beattie, M.R. Moore, A. Goldberg and A.G. Reid,
1977. "Renal insufficiency associated with excessive lead exposure."
British Medical Journal ±:482-485.
Casarett, L.J. and J. Doull, editors, 1975. Toxicology: The Basic
Science of Poisons. MacMillian Publishing Co., Inc., New York.
Center for Disease Control (CDC), 1975. "Increased lead absorption
and lead poisoning in young children." Journal of Pediatrics 87(5):
824-830.
Center for Disease Control (CDC), 1978. Preventing Lead Poisoning in
Young Children. U.S. Department of Health, Education, and Welfare,
Center for Disease Control, Atlanta, Georgia.
Chamberlain, A.C., W.S. Clough, M.J. Heard, D. Newton, A.N.B. Stott
and C.C. Wells, 1975a. "Uptake of lead by inhalation of motor
exhaust." Proceedings of the Royal Society of London B. 192:77-110.
Chamberlain, A.C., W.S. Clough, M.J. Heard, D. Newton, A.N.B. Stott
and A.C. Wells, 1975b. "Uptake of inhaled lead from motor exhaust."
Postgraduate Medical Journal 51:790-794.
Chisolm, J.J., Jr., 1962. "Aminoaciduria as a manifestation of renal
tubular injury in lead intoxication and a comparison with patterns of
aminoaciduria seen in other diseases." Journal of Pediatrics 60:
1-17.
Chisolm, J.J., Jr., 1971. "Screening techniques for undue lead expo-
sure in children: biological and practical considerations." Journal
of Pediatrics 21= 719-725.
Chisolm, J.J., M.B. Barrett and E.D. Mellits, 1975. "Dose-effect and
dose-response relationships for lead in children." Journal of Pedia-
trics 87(6):1152-1160.
134
-------
Coogan, P.S., 1973. "Lead-induced renal carcinomas." Proceedings
Inst. Medicine Chicago 29;309.
Cooper, W.C., 1978. "Mortality of workers in lead production facili-
ties and lead battery plants." Paper presented at the Second Inter-
national Symposium on Environmental Lead Research, sponsored by
International Lead Zinc Research Organization, Inc., and The Univer-
sity of Cincinnati, College of Medicine, 5-7 December 1978.
Cooper, W.C. and W.R. Gaffey, 1975. "Mortality of lead workers."
Journal of Occupational Medicine 17(2);100-107.
Daines, R.H., H. Motto and D.M. Chilko, 1970. "Atmospheric lead:
its -relationship to traffic volume and proximity to highways." Envi-
ronmental Science and Technology 4_: 318-3 22.
Damstra, T., 1977. "Toxicological properties of lead." Environmen-
tal Health Perspectives 19:297-307.
Darrow, O.K. and H.A. Schroeder, 1974. "Childhood exposure to envi-
ronmental lead." Advances in Experimental Medicine and Biology,
Volume 48 M. Friedman (ed.). Plenum Press, New York.
David, 0., S. Clark and K. Voeller, 1972. "Lead and hyperactivity."
Lancet 2:900-903.
Day, J.P., M. Hart and M.S. Robinson, 1975. "Lead in urban street
dust." Nature 253:343-345.
Dillon, H.K., D.J. Wilson and W. Schaffner, 1974. "Lead concentra-
tions in human milk." American Journal of the Diseases of Children
128:491-492..
Dingwall-Fordyce, I. and R.E. Lane, 1963. "A follow study of lead
workers." British Journal of Industrial Medicine 20;313-315.
Durfor, C.W. and E. Becker, 1964. Public Water Supplies of the 100
Large-st Cities in the U.S. Water Supply Paper #1812. U.S. Geologi-
cal Surveys Washington, D.C.
Durum, W.H., 1974. Occurrence of Some Trace Metals in Surface Waters
and Groundwaters. 16th Water Quality Conference.
Durum, W.H., J.D. Hem and S.G. Heidel, 1971. Reconnaissance of
Selected Minor Elements in Surface Waters of the United States,
October 1970. Circular #643. U.S. Geological Survey, Washington,
D.C.
135
-------
Edwards, H.W., 1975. "Environmental contamination by automotive
lead." International Symposium Proceedings on Recent Advances in
the Assessment of the Health Effects of Environmental Pollutiont
Volume 3. Commission of the European Communities, Luxemburg.
Emmerson, B.T., 1968. "The clinical differentiation of lead gout
from primary gout." Arthritis and Rheumatism 11:623-634.
Faoroj R.B. and T.B. McMullen, 1977. National Trends in Trace Metals
in Ambient Air. EPA-450/1-77-003. U.S. Environmental Protection
Agency, Washington, D.C.
Feldman, R.G., J. Haddow, L. Kopito and H. Schwachman, 1973.
"Altered peripheral nerve conduction velocity; chronic lead intoxica-
tion in children." American Journal of the Diseases of Children
125(1):39-41.
Food and Drug Administration (FDA), 1975. Compliance Program Evalua-
tion: FY 1974 Heavy Metals in Foods Survey. FDA #7320.13C. Bureau
of Foods, Washington, D.C.
Food and Drug Administration (FDA), 1977. Compliance Program Evalua-
tion: FY 74 Total Diet Studies. FDA #7320.08. Bureau of Foods,
Washington, D.C.
Forbes, G.B. and J.C. Reina, 1972. "Effect of age on gastrointes-
tinal absorption (Fe, Sn, Pb) in the rat." Journal of Nutrition
J.02_(5): 647-652; as cited in HAS, 1976.
Friberg, L., M. Piscator, G.F. Nordberg and T. Kjellstrom, 1974.
Cadmium in the Environment, 2nd edition. CRC Press, Cleveland, Ohio.
Garber, B.T. and E. Wei, 1974. "Influence of dietary factors on the
gastrointestinal absorption of lead." Toxicology and Applied Pharma-
cology 27:685-691.
Garcia, W.J., C.W. Blessin and G.E. Inglett, 1974. "Heavy metals in
food products from corn." Cereal Chemistry 51:779-787.
Gershanik, J.J., G.G. Brooks and J.A. Little, 1974. "Blood lead
values in pregnant women and their offspring." American Journal of
Obstetrics and Gynecology 119(4);508-511.
Gething, J., 1975. "Tetramethyl lead absorption: a report of human
exposure to a high level of tetramethyl lead." British Journal of
Industrial Medicine 32:329-333.
136
-------
Goldberg, A., 1974, "Drinking water as a source of lead pollution."
Environmental Health Perspectives, May 1974.
Goldberg, A., 1975. "Review of recent advances of lead in clinical
research." Postgraduate Medical Journal 51:747-750.
Goldgraben, G., 1978. The MITRE Corporation/Metrek Division, McLean,
Virginia. Personal communication.
Goldsmith, J.R., 1974. Food Chain and Health Implications of Air-
borne Lead. NTIS II PB-248 745. California State Health and Welfare
Agency, Berkeley.
Goyer, R.A. and J.J. Chisolm, 1972. "Lead." Chapter 8 In: Metallic
Contaminants and Human Health. D.H.K. Lee, (ed.). Academic Press,
New York.
Goyer, R.A. and K.R. Mahaffey, 1972. "Susceptibility to lead
toxicity." Environmental Health Perspectives, October.
Goyer, R.A. and P. Mushak, 1977. "Lead toxicity laboratory aspects."
Advances in Modern Toxicology, Volume 2: Toxicology of Trace
Elements. R.A. Goyer and M.A. Mehlman (eds.). John Wiley and Sons,
New York.
Griffin, T.B., F. Coulston, H. Wills, J.C. Russel and J.H. Knelson,
1975. "Clinical studies of men continuously exposed to airborne
particulate lead." Lead. T.B. Griffin and J.H. Knelson (eds.).
Academic Press, New York.
Gross, S.B., 1976. "Classifying lead body burdens using Z scores."
Toxicology and Applied Pharmacology 38:345-355.
Gross, S.B., E.A. Pfitzer, D.W. Yeager and R.A. Kehoe, 1975. "Lead
in human tissues." Toxicology and Applied Pharmacology 32:638-651.
Gruden, N. and M. Stantic, 1975. "Transfer of lead through the rat's
intestinal wall." Science of the Total Environment 3:288-292.
Guyton, A.C., 1971a. "Pregnancy and lactation." Chapter 82 In:
Textbook of Medical Physiology, 4th edition. W.B. Saunders Company,
Philadelphia.
Guyton, A.C., 1971b. "Red blood cells and polycythemia." Chapter 8
In: Textbook of Medical Physiology, 4th edition. W.B. Saunders
Company, Philadelphia.
137
-------
Hall, S.K. , 1972. "Pollution and poisoning." Environmental Science
and Technology 6(l);31-35.
Hammond, P.B., 1977. "Exposure of humans to lead." Annual Revue of
Pharmacology and Toxicology 17;197-214.
Hankin, L. , G.H. Heichel and R.A. Botsford, 1974. "Lead in wrappers
of specialty foods as a potential hazard to children." Clinical
Pediatrics 13(12) ; 1064-1065.
Hardy, H.L. , 1965. "Lead." Symposium on Environmental Lead Contam-
ination. NTIS #PB-198-104. U.S. Public Health Service.
Harris, P. and M.R. Holley, 1972. "Lead levels in cord blood." Pedi
atrics 49:606.
Harris, R. and W.R. Elsea, 1967. "Ceramic glaze as a source of lead
poisoning." Journal of the American Medical Association 202(6); 1297.
Harrison, P.R. , 1973. "Air pollution by lead and other trace
metals . " Advances in Experimental Medicine and Biology 40: 1 73-237 .
Hem, J.D. and W.H. Durum, 1973. "Solubility and occurrence of lead
in surface waters." Journal of the American Water Works Association
: 562-5 68.
Hernberg, S. , 1976. "Biochemical, subclinical and clinical responses
to lead and their relationship to different expsosure levels, as
indicated by the concentration of lead in blood." Effects and Dose-
Response Relationships of Toxic Metals. G.F. Nordberg (ed.).
Elsevier Scientific Publishing Company, New York.
Hernberg, S., J. Nikkanen, G. Mellin and H. Lilius, 1970. "6-Amino-
levulinic acid dehydratase as a measure of lead exposure." Archives
of Environmental Health 21; 140-145.
Huntzicker, J. J. , S.K. Friedlander and C.I. Davidson, 1975. "Mate-
rial balance for automobile-emitted lead in Los Angeles basin."
Environmental Science and Technology ^_(5) : 448-456.
Idaho Department of Health and Welfare, 1977. Shoshone Lead Health
Project Work Summary, January 1976. Division of Health, Boise,
Idaho.
International Agency for Research on Cancer (IARC), 1972. IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to Man,
Volume 1. IARC, Lyon, France.
138
-------
International Committee on Radiological Protection (ICRP), 1975.
Report of the Task Group on Reference Man; Report #23. Pergamon
Press, New York.
Jenkins, D.W., editor, 1976. Design of Pollutant-Oriented Integrated
Monitoring Systems; A Test CaseEnvironmental Lead. EPA-6QO74-76-
018. U.S. Environmental Protection Agency, Washington, D.C.
Johnson, D.E., J.B. Tillery and R.J. Prevost, 1975a. "Levels of
platinum, palladium and lead in populations of southern California."
Environmental Health Perspectives 12:27-33.
Johnson, D.E., J.B. Tillery and R.J. Prevost, 1975b. "Trace metals
in occupationally and nonoccupationally exposed individuals." Envi-
ronmental Health Perspectives IQj 151-158.
Johnson, D.E., R.J. Prevost, J.B. Tillery, K.T. Kimball and J.M.
Hosenfeld, 1978. Epidemiologic Study of the Effects of Automobile
Traffic on Blood Lead Levels. EPA-600/1-78-055. U.S. Environmental
Protection Agency, Office of Research and Development, Research
Triangle Park, North Carolina.
Joselow, M.M., J.E. Bauta, W. Fisher and J. Valentine, 1975. "Envi-
ronmental contrasts: blood lead levels of children in Honolulu and
Newark." Journal of Environmental Health 37:10-13.
Kanisawa, M. and H.A. Schroeder, 1969. "Life-term studies on the
effect of trace elements on spontaneous tumors in mice and rats."
Cancer Research 29:892-895.
Karhausen, L., 1972. "Intestinal lead absorption." International
Symposium on Environmental Health Aspects of Lead, Amsterdam.
Kehoe, R.A., 1961. "The Harben Lectures, 1960: the metabolism of
lead in man in health and disease." Journal of the Royal Institute
of Public Health and Hygiene, April-August 1961.
Kehoe, R.A., 1964. "Normal metabolism of lead." Archives of Environ-
mental Health 8_:44-47.
Kehoe, R.A., 1969. "Toxicological appraisal of lead in relation to
the tolerable concentration in the ambient air." Journal of the Air
Pollution Control Association 19_(9) -.690-701.
King, B.C., 1971. "Maximum daily intake of lead without excessive
body lead-burden in children." American Journal of the Diseases of
Children 122:337-340.
139
-------
Kirkpatrick, D.C. and D.E. Coffin, 1973. "Cadmium, lead and mercury
content of various cured meats." Journal of the Science of Food and
Agriculture 24: 1595-1598.
i
Klein, P.S., G.B. Forbes and P.R. Nader, 1975. "Effects of starva-
tion in infancy (pyloric stenosis) on subsequent learning abilities."
Journal of Pediatrics 87:8-15.
Knelson, J.H., 1974. "Problem of estimating respiratory lead dose in
children." Environmental Health Perspectives Experimental Issue No.
7_:53-57.
Kolbye, A.C., K.R. Mahaffey, J.A. Fiorino, P.C. Corneliussen and C.F.
Jelinek, 1974. "Food exposures to lead." Environmental Health Per-
spectives Experimental Issue No. 7:65-74.
Kopp, J.F. and R.C. Kroner, 1967. Trace Metals in Waters of the
United States. U.S. Department of the Interior, Federal Water Pol-
lution Control Administration, Cincinnati, Ohio.
Kopple, J.D., M.B. Rabinowitz and G.W. Wetherill, 1976. "The rela-
tive contributions of inspired and dietary lead to body lead burden."
Clinical Implications of Air Pollution Research. A.J. Finkel (ed.).
AMA/Publishing Science Group.
Kostial, K. and B. Momcilovic, 1974. "Transport of lead-203 and
calcium-47 from mother to offspring." Archives of Environmental
Health 29(1);28-30.
Kostial, K., I. Simonovic and M. Pisonic, 1971. "Reduction of lead
absorption from the intestine in newborn rats." Environmental
Research 4_: 360-363.
Krigman, M.R. and E.L. Hogan, 1974. "Effect of lead intoxication on
the postnatal growth of the rat nervous system." Environmental
Health Perspectives Experimental Issue No. 7;187-199.
Lagerwerff, J.V. and A.W. Specht, 1970. "Contamination of roadside
soil and vegetation with cadmium, nickel, lead and zinc." Environ-
mental Science and Technology 4_: 583-586.
Lamm, S.H. and J.F. Rosen, 1974. "Lead contamination in milks fed to
infants: 1972-1973." Pediatrics 53(2):137-141.
Lamola, A.A. and T. Yamane, 1974. "Zinc protoporphyrin in the
erythrocytes of patients with lead intoxication and iron deficiency
anemia." Science 186:936-938.
140
-------
Lamola, A.A., M. Joselow and T. Yamane, 1975a. "Zinc protoporphyrin
in the erythrocytes of patients with lead intoxication and iron
deficiency anemia." Science 186:936-938.
Lamola, A.A., M. Joselow and T. Yamane, 1975b. "Zinc protoporphyrin
(ZPP): a simple, sensitive fluorometric screening test for lead
poisoning." Clinical Chemistry 2Ul):93-97.
Landrigan, P.J. , S.H. Gehlbach, B.F. Rosenblum, J.M. Shoults, R.M.
Candelaria, W.F. Barthel, J.A. Liddle, A.L. Smrek, N.W. Staehling and
J.F. Sanders, 1975. "Epidemic lead absorption near an ore smelter."
New England Journal of Medicine 292(3);123-129.
Lassovszky, P., 1978. U.S. Environmental Protection Agency, Office
of Water Supply, Washington, D.C. Personal Communication.
Lee, R.E. and D.J. von Lehmden, 1973. "Trace metal pollution in the
environment." Journal of the Air Pollution Control Association
23_(1): 853-857.
Lepow, M.L., L. Bruckman, R.A. Rubino, S. Markowitz, M. Gillette and
J. Kapish, 1974. "Role of airborne lead in increased body burden of
lead in Hartford children." Environmental Health Perspectives 7;
99-102.
Lin-Fu, J.S., 1972. "Undue absorption of lead among childrena new
look at an old problem." New England Journal of Medicine 286(13):
702-710.
Lourie, R.S., E.M. Layman and F.K. Millican, 1963. "Why children eat
things that are not food." Children 10;143-146.
Lucas, J.M., 1977. Effect of Analytical Variability on Measurements
of Population Blood Lead Levels. E.I. du Pont de Nemours & Company,
Wilmington, Delaware.
Mahaffey, K.R., 1977. "Relation between quantity of lead ingested
and health effects of lead in humans." Pediatrics 59(3):448-456.
Mahaffey, K.R., P.E. Corneliussen, C.F. Jelinek and J.A. Fiorino,
1975. "Heavy metal exposure from foods." Environmental Health
Perspectives, December 1975.
Mao, P. and J.J. Molner, 1967. "The fine structure and histochem-
istry of lead-induced renal tumors in rats." American Journal of
Pathology 50:571.
141
-------
McCabe, L.J., J.M. Symons, R.D. Lee and G.G. Robeck, 1970. "Survey
of community water supply systems." Journal of the American Water
Works Association 62;670-687.
McClain, R.M. and J.J. Siekierka, 1975. "The placental transfer of
lead-chelate complexes in the rat." Toxicology and Applied Pharma-
cology 31_: 443-451.
McMullen, T.B., R.B. Faoro and G.B. Morgan, 1970. "Profile of pollu-
tant fractions in nonurban suspended particulate matter." Journal of
the Air Pollution Control Association _20(6);369-372.
Mehani, S., 1966. "Lead retention by the lungs of lead-exposed
workers." Annals of Occupational Hygiene 9:165-171.
Michaelson, I.A. and M.W. Sauerhoff, 1974. "Animal models of human
disease: severe and mild lead encephalopathy in the neonatal rat."
Environmental Health Perspectives Experimental Issue No. 7;201-225.
Millican, F.K., E.M. Layman, R.S. Lourie, L.Y. Takahashi and C.C.
Dublin, 1962. "The prevalence of ingestion and mouthing of nonedible
substances by children. Clinical Proceedings of the Children's
Hospital 18(8)-.207-214.
Mitchell, D.G. and K.M. Aldous, 1974. "Lead content in foodstuffs."
Environmental Health Perspectives Experimental Issue No. 7;59-64.
Momcilovic, B. and K. Kostial, 1974. "Kinetics of lead retention and
distribution in suckling and adult rats." Environmental Research 8:
214-220.
Moore, J.F., R.A. Goyer and M.H. Wilton, 1973. "Lead induced inclu-
sion bodies: solubility, amino acid content and acidic nuclear
proteins." Laboratory Investigations 29:488-494.
Moore, M.R., 1975. "Lead in drinking water and its significance to
health." Drinking Water Quality and Public Health, Water Research
Center.
Moore, M.R., 1977. "Lead in drinking water in soft water areas
health hazards." Science of the Total Environment 7:109-115.
Moore, M.R., P.A. Meredith and A. Goldberg, 1977. "A retrospective
analysis of blood-lead in mentally retarded children." Lancet, April
2, 1977:717-719.
Morgan, J.M., M.W. Hartley and R.E. Miller, 1966. "Nephropathy in
chronic lead poisoning." Archives International Medicine 118:17-29.
142
-------
Morse, R.S. and G.A. Welford, 1971. "Dietary intake of 210Pb."
Health Physics 21:53-55.
Murthy, G.K. and V.S. Rhea, 1971. "Cadmium, copper, iron, lead,
manganese and zinc in evaporated milk, infant products and human
milk." Journal of Dairy Science 54(7);1001-1005.
National Academy of Sciences (NAS), 1972. Airborne Lead in Perspec-
tive. Committee on the Biologic Effects of Atmospheric Pollutants,
National Research Council, Washington, D.C.
National Academy of Sciences (NAS), 1976. Recommendations for the
Prevention of Lead Poisoning in Children* Committee on Toxicology,
Assembly of Life Sciences, National Research Council, Washington,
D.C.
National Academy of Sciences (NAS), 1977. Drinking Water and Health.
Safe Drinking Water Committee, Washington, D.C.
Needleman, H.L. and S. Piomelli, 1978. The Effects of Low Level Lead
Exposure. Natural Resource Defense Council, Inc., Publication, April
25, 1978.
Nozaki, K., 1966. "Method for studies on inhaled particles in human
respiratory system and retention of lead fume." Industrial Health
(Japan) 4_: 118-128.
Olson, K.W. and R.K. Skogerboe, 1975. "Identification of soil lead
compounds from automotive sources." Environmental Science and Tech-
nology 9(3)-.227-236.
Oyasu, R., H.A. Battifora, R.A. Clasen, J.H. McDonald and G.M. Hass,
1970. "Induction of cerebral gliomas in rats with dietary lead sub-
acetate and 2-acetylaminofluorene." Cancer Research 30:1248-1261.
Patterson, C.C., 1965. "Contaminated and natural lead environments
of man." Archives of Environmental Health 11:344-360.
Perkins, K.C. and F.A. Oski, 1976. "Elevated blood lead levels in a
6-month-old breast-fed infant: the role of newsprint logs."
Pediatrics 57(3) -.426-427.
Pierce, J.O., S.R. Koirtyohann, I.E. Clevenger and F.E. Lichte, 1976.
The Determination of Lead in Blood...A Review and Critique of the
State-of-the-Art, 1975. International Lead Zinc Research Organiza-
tion, Inc., New York.
143
-------
Pioraelli, S., 1978. Director, Pediatric Hematology, New York Univer-
sity Medical Center, New York, New York. Letter to J. Padgett,
Director of Standards, Air Strategy Division, U.S. Environmental Pro-
tection Agency, Research Triangle Park, North Carolina, dated 14
March 1978.
Piomelli, S., B. Davidow, V.F. Guinee, P. Young and G. Gay, 1973.
"The FEP (free erythrocyte porphyrins) test: a screening taicromethod
for lead poisoning." Pediatrics 51(2):254-259.
Preston, E., 1977. Ambient Lead Concentrations in the United States:
Air Quality Control Regions with Monitoring Data. WP-12068. The
MITRE Corporation/Metrek Division, McLean, Virginia.
Quarterman, J., J.W. Morrison and W.R. Humphries, 1976. "The effects
of dietary lead content and food restriction on lead retention in
rats." Environmental Research 12:180-187.
Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple, 1973. "Lead
metabolism in the normal human: stable isotope studies." Science
182:725-727.
Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple, 1974. "Studies of
human lead metabolism by use of stable isotope tracers." Environ-
mental Health Perspectives Experimental Issue No. 7:145-153.
Rabinowitz, M., G.W. Wetherill and J. Kopple, 1975. "Absorption,
storage and excretion of lead by normal humans." Trace Substances in
Environmental Health, Volume IX. D.D. Hemphill (ed.). University of
Missouri, Columbia, Missouri.
Rastogi, S.C. and J. Clausen, 1976. "Absorption of lead through the ,
skin." Toxicology 6:371-376.
Roberts, E., R. Spewak, S. Stryker and S. Tracy, 1975. Collection
and Analysis of Toxic Substances Data from State Agencies, Volume 4.
M75-52. The MITRE Corporation/Metrek Division, McLean, Virginia.
Roberts, T.M., T.C. Hutchinson, J. Paciga, A. Chattopadhyay, R.E.
Jervis, J. Van Loon and O.K. Parkinson, 1974. "Lead contamination
around secondary smelters: estimation of dispersal and accumulation
by humans." Science 186:1120-1123.
Robinson, E. and F.L. Ludwig, 1967. "Particle size distribution of
urban lead aerosols." Journal of the Air Pollution Control Associa-
tion 17:664-669.
144
-------
Roe, F.J.C., E. Boyland, C.E. Dukes and B.C.V. Mitchley, 1965.
"Failure of testosterone or xanthopterin to influence the induction
of renal neoplasms by lead in rats." British Journal of Cancer
19:860-866.
Rolfe, G.L. and A. Haney, 1975. An Ecosystem Analysis of Environ-
mental Contamination by Lead. Institute for Environmental Studies,
Research Report #1, University of Illinois at Urbana, Champaign,
Illinois".
Rosen, J.F. and E.E. Wexler, 1977. "Studies of lead transport in
bone organ culture." Biochemical Pharmacology 26:650-652.
Sabotkaj T.J. and M.P. Cook, 1974. "Postnatal lead acetate exposure
in rats: possible relationship to minimal brain dysfunction." Amer-
ican Journal of Mental Deficiency 79;5-9.
Sachs, H.K., 1975. Letter to Dr. J. Julian Chisolm, Jr. dated 18
October 1975; as cited in NAS, 1976.
Sandhu, S.S. , P. Nelson and W.J. Warren, 1975. "Potable water qual-
ity in rural Georgetown County." Bulletin of Environmental Contam-
ination and Toxicology J^4_(4) :465-472.
Schroeder, H.A. and J.J. Balassa, 1961. "Abnormal trace metals in
man: lead." Journal of Chronic Diseases 14(4):408-425.
Schroeder, H.A. and I.H. Tipton, 1968. "The human body burden of
lead." Archives of Environmental Health 17_;965-978.
Sehmel, G.A., 1976. "Particle resuspension from an asphalt road
caused by car and truck traffic." Proceedings of the Symposium on
Atmosphere-Surface Exchange of Particulate and Gaseous Pollutants.
Richland, Washington. ERDA Symposium Series (38):859-882.
Seppalainen, A.M., S. Tola, S. Hernberg and B. Kock, 1975. "Sub-
clinical neuropathy at safe levels of lead exposure." Archives of
Environmental Health 30;180-183.
Shier, D.R. and W.G. Hall, 1977. Analysis of Housing Data Collected
in a Lead-Based Paint Survey in Pittsburgh, Pennsylvania. National
Bureau of Standards, Washington, D.C.
Singerman, A., 1976. "Clinical signs versus biochemical effects for
toxic metals." Effects and Dose-Response Relationships of Toxic
Metals. G.F. Nordberg (ed.). Elsevier Scientific Publishing
Company, Amsterdam.
145
-------
Smith, R.G., 1971. "Health aspects of atmospheric exposure to lead."
Medical Aspects of Air Pollution. SAE, Inc.
Steiglitz, E.J., 1949. Geriatric Medicine. W.B. Saunders Company,
Philadelphia.
Stiller, D., 1973. "Topochemie tubularer Enzymanuster wahrend der
experimentalien Cancerisierung. Untersuchungen zur Enzymhistochemie
der chronischen BLeinephropathie der Ratte." Experimental Pathology
8.: 137-153.
Stoewsand, G.S., 1972. Toxic Metals in Our Food Chain. New York
State Association of Milk and Food Sanitarians, New York.
Strain, W.H., A. Flynn, E.G. Manson, F.R. Plecha, W.J. Pories and
O.A. Hill, Jr., 1975. "Trace element content of household water."
Trace Substances in Environmental Health. Volume IX. D.D. Hemphill
(ed.). University of Missouri, Columbia, Missouri.
Sundennan, F.W., Jr., 1971. "Metal carcinogenesis in experimental
animals." Food and Cosmetics Toxicology 9:105-120.
Task Group on Lung Dynamics, 1966. "Deposition and retention models
for internal dosimetry of the human respiratory tract." Health
Physics 12.: 173-307.
Task Group on Metal Toxicity, 1976. "Dose." Effects and Dose-
Response Relationships of Toxic Metals. G.F. Nordberg (ed.).
Elsevier Scientific Publishing Company, Amsterdam.
Tepper, L.B. and L.S. Levin, 1975. "A survey of air and population
lead levels in selected American communities." Environmental Quality
and Safety, Supplement II; Lead.
Ter Haar, G. and R. Aronow, 1974. "The use of tracer techniques and
environmental sources for evaluation of the lead problem in
children." Recent Advances in the Assessment of the Health Effects
of Environmental Pollution. World Health Organization, Luxembourg.
Ter Haar, G,L. and M.A. Bayard, 1971. "Composition of airborne par-
ticulates." Nature 232:553-554.
Thomas, B., J.A. Roughan and E.D. Waters, 1972. "Lead and cadmium
content of some vegetable foodstuffs." Journal of Food Science and
Agriculture 23_: 1493-1498.
146
-------
Thomas, B., J.A. Roughan and E.D. Waters, 1973. "Lead and cadmium
content of some canned fruit and-vegetables." Journal of Food Sci-
ence and Agriculture 24;447-449.
Thomas, B., J.W. Edmunds and S.J. Curry, 1975. "Lead content of
canned fruit." Journal of Food Science and Agriculture 26:1-4.
Thompson, J.A., 1971. "Balance between intake and output of lead in
normal individuals." British Journal of Industrial Medicine 28:189-
194.
Tola, S., S. Hernberg, S. Asp and J. Nikkanen, 1973. "Parameters
indicative of absorption and biological effect in new lead exposure:
a prospective study." British Journal of Industrial Medicine 30;134-
141.
Tola, S. and C.H. Nordman, 1977. "Smoking and blood lead concentra-
tions in lead-exposed workers and an unexposed population." Environ-
mental Research 13:250-255.
Tolan, A. and G.A.H. Elton, 1972. "Lead intake from food." Inter-
national Symposium on Environmental Health Aspects of Lead,
Amsterdam.
Tolley, J.A., 1973. "Total lead in drinking water." Lancet 2(844):
1497-1498.
de Treville, R.T.P., 1964. "Natural occurrence of lead." Archives
of Environmental Health 8_:212-221.
Tsuchiya, K., 1977. Toxicology of Metals: Lead. EPA-600/1-77-022.
U.S. Environmental Protection Agency, Washington, B.C.
U.S. Environmental Protection Agency (EPA), 1972a. EPA's Position on
the Health Effects of Airborne Lead. U.S. Environmental Protection
Agency, Washington, B.C.
U.S; Environmental Protection Agency (EPA), 1972b. Helena Valley,
Montana, Area Environmental Pollution Study. Report #AP-91. U.S.
Environmental Protection Agency, Office of Air Programs, Research
Triangle Park, North Carolina.
U.S. Environmental Protection Agency (EPA), 1975. Chemical Analysis
of Interstate Carrier Water Supply Systems. EPA 430/9-75-005'. U.S.
Environmental Protection Agency, Washington, D.C.
U.S. Environmental Protection Agency (EPA), 1977. Air Quality Cri-
teria for Lead. EPA-600/8-77-017. U.S. Environmental Protection
Agency, Washington, D.C.
147
-------
U.S. Environmental Protection Agency (EPA), 1978a, Environmental
Impact Statement [Lead]. U.S. Environmental Protection Agency,
Office of Air, Noise, and Radiation, Office of Air Quality Planning
and Standards, Research Triangle Park, North Carolina, September.
U.S. Environmental Protection Agency (EPA), 1978b. National Ambient
Air Quality Standard for Lead. U.S. Environmental Protection Agency,
Office of Air, Noise, and Radiation, Office of Air Quality Planning
and Standards, Research Triangle Park, North Carolina, September.
Van Esch, G.J. and R. Kroes, 1969. "The induction of renal tumours
by feeding basic lead acetate to mice and hamsters." British Journal
of Cancer 23;765-770.
Van Esch, G.J., H. van Gendern and H.H. Vink, 1962. "The induction
of renal tumours by feeding basic lead acetate to rats." British
Journal of Cancer 16:289-297.
Waldron, H.A. and D. Stofen, 1974. Sub-Clinical Lead Poisoning.
Academic Press, New York.
Wessel, M.A. and A. Dominski, 1977. "Our children's daily lead."
American Scientist 65;294-298.
s
WeCherill, G.W., M.B. Rabinowitz and J.D. Kopple, 1974. "Sources and
metabolic pathways of lead in normal humans." Recent Advances in the
Assessment of the Health Effects of Environmental Pollution, Volume
2. Proceedings of the International Symposium, Paris, June 24-28,
pp. 847-860.
Wong, C.S. and P. Berrang, 1976. "Contamination of tap water by lead
pipe and solder." Bulletin of Environmental Contamination and Toxi-
cology 15(5):530-534.
World Health Organization (WHO), 1977. Environmental Health Criteria
3Lead. World Health Organization, Geneva.
Yamaguchi, S., S. Kaku, Y. Hirota, S. Matuo, H. Matsumoto and N.
Shimojo, 1976. "An appraisal of the changes in delta-aminolevulinic
acid dehydrase activity for an assessment of health effects at
several levels of environmental lead." Effects of Dose-Response
Relationships of Toxic Metals. G.F. Nbrdberg (ed.). Elsevier Scien-
tific Publishing Company, New York.
Yankel, A., I.H. von Lindern and S.D. Walter, 1977. "The Silver
Valley study: the relationship between childhood blood lead levels
and environmental exposure." Journal of the Air Pollution Control
Association 27(8):763-767.
148
-------
Zawirska, B. and K. Medras, 1968. "Tumors and disorders of porphyrin
metabolism in rats with chronic experimental lead poisoning."
Zentbl. Allg. Path. 111:1-12.
Ziegler, E.E., B.B. Edwards, R.L. Jensen, K.R. Mahaffey and S.J.
Fomon, 1978. "Absorption and retention of lead by infants."
Pediatric Research 12(1);29-34.
Zielhuis, R.L., 1975. "Dose-response relationships for inorganic
lead: I. biochemical and haematological responses; II. subjective
and functional responseschronic sequelae no-response levels."
International Archives of Occupational Health 35:1,19.
Zollinger, H.U., 1953. "Durch chronische Bleivergiflung erzeugte
Nierenadenome und-carcinome bei Ratten und ihre Beziehungen zu den
entsprechenden Neubildunger des Menschen." Virchows Arch. Path.
Anat. 323:694-710.
149
-------