Lead Exposure and Human Health

The Toxicity of Lead

Lead is one of a limited
class of elements that can
be described as purely toxic.
Many other elements,
including heavy metals
such as chromium, manganese, molybdenum, nickel,
and selenium, although
toxic at high levels, are
actually required nutrients
at lower levels. This is
clearly not the case for lead.
In many decades of research, no nutritional value
or positive biological effect
has been shown to result
from lead exposure. Neither
has any case of lead deficiency ever been noted in
the medical literature.

ate doses has been known

for millennia; toxicity at
lower doses has received
perhaps more toxicological
and epidemiological attention than any other agent:

The literature on lead

toxicity is far too vast to
review in this paper. Instead, this section summarizes the international
scientific consensus, based
on comprehensive evaluations of the literature
conducted by international
organizations and national
governments (for example,
20, 25, 49, 53).

Studies on the toxicity of

lead can be grouped into
three broad categories:

How Do We Know
Lead is Toxic?
Of all of the toxic chemicals
known to humanity, lead is
probably the most thoroughly studied. The toxicity
of lead at high and moder-

If we were to judge of the

interest excited by any
medical subject by the
number of writings to
which it has given birth,
we could not but regard
the poisoning by lead as
the most important to be
known of all those that
have been treated of, up
to the present time.
(Orfilia, 1817, cited in
Goyer [20])

studies of worker exposure and of populations

known to have been
exposed to elevated lead
levels,

epidemiological studies in

Occupational studies of lead

poisoning are perhaps the
most numerous. This
reflects not only the widespread use of lead for many
different industrial purposes, but also the absence
of effective exposure controls for workers in many
industrial settings. Sadly,
this is not merely a historical problem; cases of severe
lead poisoning in workers
continue to occur in the
international medical
literature.
Where a single large industrial facility or many small
industries, lacking appropriate controls for environmental emissions, are
located close to residences,
local populations are found
who have elevated body
burdens of lead. These
exposed population studies
are probably the second
most numerous type of
investigation in the toxicological literature, after
occupational studies.

the general population,

animal studies investigating mechanisms of toxicity.

These three types of studies
have yielded consistent
conclusions about the
toxicity of lead:

Studies of populations with

known exposures to lead
have not resulted in finding
a safe exposure level. This
realization has led in this
century to epidemiological
studies addressing lead
exposures and effects in the
general population and
particularly in children. The

Global Opportunities for Reducing the Use of Leaded Gasoline

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Figure 1

Organ Systems Affected by Lead

ENCEPHALOPATHY (severe, debilitating
neurological impairment)
sensory deficits
IQ / learning disruption

ISCHAEMIC HEART DISEASE (caused

by obstruction of blood supply)
hypertension

INTERSTITIAL NEPHRITIS
(chronic inflammatory kidney
disease, causing loss of function)
decreased reabsorption

PERIPHERAL NEUROPATHY (breakdown

in sensory or motor communication)
decreased nerve conduction velocity
(speed at which nerves transmit
messages)

ANEMIA
biochemical disruption
of heme synthesis
(heme is the molecule that
enables blood to carry oxygen)

in men:

in women:
ABNORMALITIES IN OFFSPRING
diminished fertility

TESTICULAR ATROPHY
hypospermia
(decreased sperm counts)

HIGHER DOSE MORE SEVERE EFFECT

lower dose less severe effect
Extensive study shows NO evidence of threshold or safe exposure

initial studies predominantly looked at crosssections of the population,

that is people with a range
of body
burdens at a
Lead is highly toxic
particular
point in
and has no known
time. These
beneficial effects in
have been
the body.
supplemented in
recent years
by a number
of long-range (longitudinal)
studies that examined lead
body burdens and toxicity in
a defined population over
several years. Longitudinal
studies provide valuable
additional information on
whether particular toxic
effects may be reversed.

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With human studies, it is

extremely difficult to assess
exposure accurately and
impossible to assess causes.
Animal studies are therefore
used to identify the mechanisms by which lead is
toxic. Findings from these
studies have proven consistent with data from human
studies, although many
experimental animals
appear to be less sensitive
than humans to the toxicity
of lead. For some effects,
this may reflect differences
in the sensitivity of the test
methods employed.

How is Lead Toxic?

Lead has been demonstrated to be toxic to a wide
variety of organs in both

humans and experimental

animals. The organ systems
that have been shown to be
most sensitive to low-level
exposures of lead are
illustrated in Figure 1.
Other effects include:

Nervous

System: Changes
in neurotransmitter levels

Biochemistry: Impairment
of Vitamin D metabolism

Reproductive

System:
irregular estrus and
decreased sexual hormone
levels

Immune

System: impaired
lymphocyte function and
impaired antibody formation

Global Opportunities for Reducing the Use of Leaded Gasoline

 Gastrointestinal: colic
(severe cramping and
nausea; characteristic of
high-dose poisoning)

Reproductive: decreased
gestation duration and
decreased growth rate in
offspring
There is also clear evidence
that lead can cause cancer
in experimental animals.
Thus, the US Environmental Protection Agency has
classified lead as a probable human carcinogen
(Group B2), and the International Agency for Research on Cancer has
deemed it possibly carcinogenic to humans (Group
2B). The characteristic
tumor observed in animals
has been a bilateral renal
carcinoma, although other
sites and tumor types have
been observed. While the
cancers observed in animals

How is
Lead
Exposure
Measured?

may be secondary to other

forms of toxicity, there is
also evidence for a direct
effect of lead on genetic
material. Data from studies
of worker exposure have
been inconsistent with
regard to cancer.

How Toxic is Lead?

Because lead has been
widely used for millennia, it
is widely distributed in the
environment and can be
detected globally in air, soil,
and water. Because there is
no level of lead exposure
that appears to be necessary or beneficial, considerable research interest has
focused on the question of
whether there is any level of
exposure that is harmless,
and if so, what that level
might be.

Various types of effect have

been noted at different
levels of exposure, as
illustrated in Tables 1 and
2, which contain only data
cited in authoritative references. In a number of cases,
variations in study design
and the
population
Lead is toxic at very
studied have
low exposures.
led to
slightly
different
Eve n t h e l ow est
conclusions.

doses can impair

the nervous system.

One consequence of
the extensive investigation of the toxic effects of
lead, using increasingly
sensitive measurements ,
has been the development of
a scientific consensus that
there is no demonstrable
threshold dose for the
manifestation of leads
toxicity. In other words,

Most people are exposed to more than one source of lead.

Accordingly, even when a single environmental medium (for
example, air or soil) is the predominant source of lead exposure
for a population, measurements in that medium alone may not
yield an accurate estimate of the populations full exposure to
lead.
For this reason, the vast majority of studies of the toxic effects of
lead in humans rely on direct estimates of the body burden of
lead. Most commonly, lead levels in whole blood are measured.
These measurements of blood lead (PbB) are generally expressed
as micrograms of lead per deciliter of blood (g/dl).
Such blood lead levels are more reflective of ongoing or recent
lead exposure than of the full history. (Lead tends to be taken up
by bone, so that even if the total amount of lead in the body
does not change, blood lead levels will decrease over time). For
this reason, some studies of populations that are believed to have
been exposed to lead over prolonged periods rely on alternative
measurements of body burden. For example, studies in
schoolchildren have often analyzed lead levels in deciduous teeth.

Global Opportunities for Reducing the Use of Leaded Gasoline

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Table 1

Toxic Effects of Lead in Adults

Nervous system: overt clinical encephalopathy

100-120

Kidney: atrophy and interstitial nephritis

40-100

Gastrointestinal: colic

40-60

Formation of blood cells: anemia

50

Reproductive system: hypospermia, testicular atrophy

40-50

Nervous system: IQ/learning disruption,

sensory system deficits

40

Heart and blood vessels: hypertension

<7 *

Formation of blood cells: biochemical (enzyme changes)

3-30 *

Blood lead levels in micrograms of lead per deciliter of blood (

(g/dl)
* No evidence of threshold

there is no exposure level

below which lead appears to
be safe. If a safe level exists,
current testing techniques
are not yet sensitive enough
to find it.
This distinNo safe level of
guishes lead
exposure to lead has
from most
been found.
chemicals
that cause
non-cancer
toxic effects,
where the consensus is that
at some non-zero exposure,
effects are negligible. The
US EPA concluded:
It appears that some of
these effects, particularly
changes in the levels of
certain blood enzymes
and in aspects of
childrens neurobehavioral
development, may occur
at blood levels so low as
to be essentially without a
threshold. (53)

On this basis, EPA declined

to specify a Reference Dose
(that is, a level of exposure
not likely to lead to adverse
effects) for lead. Similarly,
the US Agency for Toxic
Substances and Disease

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10

Registry (ATSDR) has not

developed Minimum Risk
Levels for lead, because no
thresholds have been
demonstrated for the most
sensitive effects in humans. For lead, therefore,
any exposure is of potential
concern.
The extensive history of lead
use, however, also means
that lead is ubiquitous. This
metal has been used so
widely and so long that it
now appears essentially
everywhere.
In combination with the
lack of evidence for a safe
threshold and the limited
sensitivity of the techniques
employed to study lead, this
means that the toxicologist
is always faced with the
problem not of determining
whether any exposure will
lead to an effect, but
whether the effect, quantitatively and qualitatively,
will be deemed significant in
a particular context. Key
areas where international
scientific consensus has not
yet developed relate to the

exposures at which effects

in various organ systems
begin to affect human
health and become medically significant.

To Whom is Lead Toxic?

One area of scientific agreement is that children are
uniquely susceptible to the
effects of lead. Indeed,
children appear to be more
sensitive to lead than adults
in all areas except kidney
function. The most critical
sphere for children is the
potential for damage to their
intellectual and behavioral
development. This appears
to reflect three key factors:

Young children behave in

ways that increase their
exposure.

Children absorb more lead

for a given exposure than
do adults.

Developing organisms are

inherently more susceptible than mature ones.

Global Opportunities for Reducing the Use of Leaded Gasoline

Childrens Susceptibility to Leads Toxicity

dusty
fingers to
mouth

Figure 2

critical period for

neural connectors
blood/brain
barrier
highly
permeable

greater
gastrointestinal
absorption
and retention

poor diets will also increase toxic effects

This constellation of factors

is illustrated in Figure 2.
Greater Exposure
Between the ages of one and
three, children engage in
oral exploration of their
environment, placing nonfood objects in their
mouths. They also put their
hands in their mouths
frequently. This normal
behavior can lead to ingestion of lead-contaminated
soil and dust. Some children exhibit pica behavior,
an abnormal or extreme
tendency to eat non-food
materials, which can lead to
even greater ingestion of
contaminants. Children also
have a higher inhalation
rate, relative to their body
mass, than do adults. This
leads to greater exposure to
airborne contaminants.

Greater Absorption
and Retention
It has been estimated that
for a given oral dose of lead,
children absorb three times
more lead than do adults.
Of this absorbed dose,
children are estimated to
retain six times as much as
do adults. (20)
Greater Vulnerability
Lead is not the only toxic
agent to show harmful
effects on the nervous
system in children at much
lower exposure levels than
for adults. One possible
factor is that the so-called
blood-brain barrier, which
protects the adult brain
from toxic agents to some
degree, is not fully developed in children. Another is
that the nervous system
undergoes tremendous
development during child-

Children are
especially sensitive
to lead
They are exposed to
more, they absorb
and retain more,
and they show
greater
damage
for a given body
burden . . .

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Table 2

Toxic Effects of Lead in Children

Kidney: atrophy and interstitial nephritis

80-120

Nervous system: overt clinical

encephalopathy

80-100

Gastrointesintal: colic

60-100

Formation of blood cells: anemia

20-40

Formation of blood cells: biochemical (enzyme) changes

< 10 *

Nervous system: IQ/learning disruption

< 10 *

Blood lead levels in micrograms of lead per deciliter of blood (

(g/dl)
* No evidence of threshold

hood, including cell proliferation, the development of

intercellular connections,
and dyingback of
. . . and children with
excess
connections.
dietary deficiencies
Interference
a re eve n m o re
by a toxic
susceptible.
agent with
these developmental
events would
be expected to have grave
and permanent influences
on the ultimate functioning
of the nervous system.
Effects Influenced
by Nutrition
Susceptibility to the toxicity
of lead also shows an
interaction with nutritional
levels. The result is that
children with inadequate
diets are most likely to be
adversely affected by lead
exposure. In part, this may

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reflect competition between

lead and calcium for absorption, so that diets low
in calcium allow greater
lead absorption. The interaction of toxicity with
nutritional status means
that in developed nations,
lead toxicity may be primarily a problem for the urban
poor. In those developing
nations where nutrient
deficiencies are a problem,
lead contamination of the
environment will have more
devastating effects than
would otherwise be the
case.

Multigenerational Concerns
Exposure to lead for women
of childbearing age can have
adverse effects on their
offspring, should they
become pregnant. Lead that
is not excreted from the
body is eventually seques-

tered in bone; almost the

entire body burden of lead
is carried in bone, rather
than blood or other tissues.
This lead can be mobilized
from bone during pregnancy. Lead also transfers
readily from the mother to
the fetus via the placenta
(umbilical cord blood lead
levels are typically very
close to maternal blood lead
levels). Thus, lead exposure
in a pregnant womans
history, even in her own
childhood, may affect her
children. Although the past
exposure may not be manifested in adverse effects on
a woman herself (because
the lead has been sequestered in bone), that exposure may pose a risk to her
future offspring (Figure 3).
(For example, 22, 25.)

Global Opportunities for Reducing the Use of Leaded Gasoline

The Control of Leads Toxicity: Standards for Lead Exposure

Given the scientific
communitys inability to
delineate a safe level of
exposure to lead, it is
perhaps not surprising that
regulations and guidelines
controlling exposure to lead
vary considerably among
nations and between national governments and
international bodies.

dard that represents a

maximum acceptable
concentration of lead in
blood, air, water, soil,
sediment, foods, etc. Concentrations of lead that
exceed such a standard may
lead to efforts to control or
rectify the corresponding
pollution or to sanctions
against a polluting facility.

Some regulatory or advisory

values appear to reflect
earlier scientific evaluations, while others are more
in accord with more recent
evidence indicating toxic
effects from lead at doses
once considered safe. In
general, these standards
have decreased steadily
through this century as
more of leads toxic potential has become known.

OECD has published information on lead standards

(or guidelines) promulgated
by individual nations,
primarily member states
(36). More recently, the
International Lead and Zinc
Study Group (ILZSG) has
compiled and published
similar data (23). Various
other documents contain
information on standards
for individual nations. In all
cases where data were
directly available from
government publications,

Regulations and guidelines

typically set forth a stan-

those official values were

used in this report. (In two
cases, data from the respective governments differed
significantly from the ILZSG
document.)

Blood Lead
As noted above, most
toxicology studies rely on
blood lead
level as the
Standards for
measure of
acceptable expoexposure.
This means
sures have steadily
that blood
decreased in this
lead levels
century.
measured in
a population
can be
compared
directly to toxicity studies.
(In contrast, when lead is
measured in air, soil, food,
etc., the results must first
be extrapolated to corre-

Effects on the Next Generation

Figure 3

Lead ingested
or inhaled in
childhood enters
the bloodstream
and accumulates
in bone.

Years later,
lead stored in
the bones may
be mobilized
during
pregnancy,
affecting the
fetus.

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sponding blood levels,

before assessment of potential effects.) Table 3 illustrates international and
national standards.
In 1980, the World Health
Organization specified a
blood lead
level of 40
Standards for lead
g/dl in the
general
exposure (blood, air,
population
water, food) vary
and 30 g/
widely from country
dl in women
of childbearto country.
ing age.
Subsequent
WHO standards have been based on
keeping levels in the vast
majority of the population
below 20 g/dl. (25)

Table 3

Official statements on limits

on blood lead for the general
population (as opposed to
workers) have been made by
several member countries of
the OECD. In Australia, the
National Health and Medical
Research Council set a
national goal for all Australians to have blood lead less
than 10 g/dl (except for
occupational exposures)
(10). Health Canada has
established a guideline of 10
g/dl, while Germany has
set a guideline of 15 g/dl
in adults, 10 g/dl in
children and women of
childbearing age. Switzerland has stated officially
that levels as low as 10-15
g/dl may have a detrimental effect on a fetus, while
prolonged levels above 10
g/dl are detrimental to

children. In the United

States, the Centers for
Disease Control (CDC) has
specified a level of 10 g/dl
as an action level for blood
lead in children, noting that
this level may be associated
with a 2.5 point decrease in
Intelligence Quotient (IQ).
In general, these standards
have been promulgated
fairly recently, and they
reflect increasing concern
over exposures to lead that
were once thought safe.
Thus, for example, the
Australian goal was set in
1993, while Canadas value
was lowered from 25 to 10
g/dl in 1994. The United
States CDC revised its
value in 1991; it had previously been set at 25 g/dl.

Standards and Guidelines: Blood Lead Levels

World Health Organization (1980) general population
women of childbearing age

40
30

WHO (since 1980)

general population

20

Germany

general population
children, women of childbearing age

15
10

Switzerland

fetus
children

Australia, Canada

general population

10

United States

children

10 **

10-15 *
10 *

Blood lead levels in micrograms of lead per deciliter of blood (

(g/dl)
* Levels stated to be potentially detrimental
** Action level

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Global Opportunities for Reducing the Use of Leaded Gasoline

Standards and Guidelines: Lead in Air

Canada (provincial standards for Newfoundland, Ontario)

5.0

South Africa

4.0

European Union Directive

Belgium, France, Germany, Ireland, Italy, Netherlands,
Spain, United Kingdom also report as national

2.0 *

Australia, Namibia, United States

1.5 **

New Zealand, Switzerland

1.0

Czech Republic, Israel

0.5

Denmark

0.4

Russian Federation

0.3

Table 4

Standards or recommendations for ambient air

g/m3)
in micrograms of lead per cubic meter of air (
* annual average
** qu arterly
The United States is considering a revision to 0.75.

Lead in Air
WHO has estimated that
long-term ambient air
concentrations of 0.5-1.0
micrograms of lead per
cubic meter of air (mg/m3)
would mean that 98 percent
of the population would
have blood lead levels below
20 g/dl. For each 1 mg/m3
increase in the air concentration of lead, the blood
lead value in children is
predicted to increase by
approximately 1.9 mg/dl
and that for adults by 1.6
mg/dl. (25)
Illustrative levels of national
standards for lead in air are

depicted in Table 4. Of the

30 nations for which ambient air values were tabulated by ILZSG, 12 reported
no standards for ambient
air, while 12 had binding
legal or regulatory standards (as opposed to guidelines or proposed standards). Six of the 12 countries with no standards for
ambient air did report legal
limits on industrial emissions, and all six had
regulations or guidelines for
workplace exposure.
As can be seen from the
figure, there is a wide range
in the concentrations of lead

in ambient air that are

considered acceptable by
different national authorities. Assuming that the
relationship between air
lead and blood lead levels
described by WHO applies
over this range, this difference in air standards would
correspond to a difference of
nine mg/dl in the accepted
average blood level of
children in these countries,
were lead concentrations in
air to remain stable at these
regulatory limits. The data
on toxic effects presented
above suggest that this
could lead to significant
differences in the incidence
of toxic effects.

Global Opportunities for Reducing the Use of Leaded Gasoline

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Table 5

Standards and Guidelines: Lead in Water

Japan, Namibia, South Africa

100

European Union Directive

50

Pre-1993 World Health Organization Guideline

50

Australia, Austria, Czech Republic, Denmark, France,

Ireland, Israel, Italy, Mexico, Netherlands, New Zealand,
Spain, Switzerland, United Kingdom, United States*

50

Germany

40

Norway

20

1993 World Health Organization Guideline

10

Canada, Finland, Sweden

10

g/l)
Standards for water in micrograms of lead per liter of water (
* In 1991, US action level set to 10% or more of samples exceeding
15 g/l.

Lead in Drinking Water

In 1984, WHO established a
drinking water guideline of
50 g/liter. In 1993, this
goal was revised to 10 g/l,
to be met in 15 years, with
an interim five-year goal of
25 g/l. Most of the OECD
countries had national
standards corresponding to
the earlier WHO guideline,
although some were more
stringent.
Table 5 illustrates data on
standards for lead in drinking water. (Many nations set
separate standards, generally less stringent, for
surface water bodies, that

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vary with the likely use of

the water body). As can be
seen, most national regulations reflect the older WHO
assessment, while a few
countries have set more
stringent standards.

Lead in Soil or Dust

Several nations have specified maximum levels of lead
in soil under various conditions. Standards have also
been promulgated for lead
content in sewage sludge
applied to soil (for example,
as fertilizer). The European
Union has specified a level

of 300 mg/kg for the former

and 1,200 mg/kg for the
latter. In general, it is
harder to characterize
national standards for soil
than for air and water. In
addition to differences
between nations, many
nations have standards
that vary according to
geographic region, soil type
(for example, pH or organic
materials content), and
intended or current land
use. Moreover, standards
for cleaning contaminated
soil are generally less
stringent than are normative standards for uncontaminated soils. (24)

Global Opportunities for Reducing the Use of Leaded Gasoline