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Biomarkers of Metal Toxicity in Population Studies:

Research Potential and Interpretation Issues
a
Alfred Bernard
a
Department of Public Health, Catholic University of Louvain, Brussels, Belgium
Published online: 06 Aug 2008.

To cite this article: Alfred Bernard (2008) Biomarkers of Metal Toxicity in Population Studies: Research Potential and
Interpretation Issues, Journal of Toxicology and Environmental Health, Part A: Current Issues, 71:18, 1259-1265, DOI:
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 Journal of Toxicology and Environmental Health, Part A, 71: 1259–1265, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1528-7394 print / 1087-2620 online
DOI: 10.1080/15287390802211885
Biomarkers of Metal Toxicity in Population Studies:
UTEH
Research Potential and Interpretation Issues
Alfred Bernard
Biomarkers Of Metal Toxicity In Population Studies
Department of Public Health, Catholic University of Louvain, Brussels, Belgium
Biomarkers of effects are molecular tools that can serve to
identify changes or effects occurring in the organism because of
exposure to a given toxicant or stressor. The potential of biomarkers
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of effects in epidemiology resides mainly in their greater sensitiv-
ity and specificity as compared with more traditional endpoints.
Noninvasiveness and objectivity are also important features of
effect biomarkers that allow minimizing of the risks of participa-
tion and response biases in population studies. Since effect biom-
arkers are not specific for a given metal, they should always be
used in combination with biomarkers or tests of exposure. Dose-
response/effect relationships emerging between effect and expo-
sure biomarkers should be carefully analyzed in order to avoid
confounding by sampling conditions, subjects’ characteristics or
lifestyle, or else recent changes in exposure levels. It is also impor-
tant to exclude the possibility of secondary associations, as well as
to make sure that metal exposure is the cause of the effect and not
the opposite (reverse causality). Assessing the health significance
of associations between effect biomarkers and metal exposure is a
delicate task, which necessarily implies some personal judgment.
Factors to consider in this exercise include the magnitude and
type of adverse effect, the possibility of some reversal, the strength
of associations, and the type and size of populations at risk.
Metals have played an important role in the development of
biomarkers and of the biomonitoring approach. M. Orfila, the
founder of toxicology, was probably the first in 1839 to use a
biomarker when he applied Marsh’s method to detect arsenic
in the bodies of victims of acute poisoning. In 1927, almost a
century later, Badham and Taylor (cited by Aitio et al., 2007)
made a further step by proposing to measure lead in urine in
the diagnosis of lead poisoning. The first biomarkers of toxic
effects were also developed following observations made on
subjects intoxicated by metals. The pioneering work of L. Friberg
in the late 1940s on the proteinuria of cadmium workers (Friberg,
Alfred Bernard is Research Director of the National Fund for
Scientific Research, Belgium. This work was supported by the
European Commission (FP6, Phime project, coordinator S. Skerfving).
Address correspondence to Alfred Bernard, Unit of Toxicology,
Faculty of Medicine, Catholic University of Louvain, Avenue
E. Mounier 53, Box 53.02, B-1200, Brussels, Belgium. E-mail:
alfred.bernard@uclouvain.be
1259
1950) paved the way to the discovery of the low-molecular-
weight proteins (e.g., β2-microglobulin and retinol-binding
protein), which now serve to screen tubular dysfunction caused
by cadmium and other toxicants. A few years later, the studies
of Haerger-Aronsen (1960) on the mechanism of lead-induced
anemia led to the identification of several biomarkers of lead
exposure based on the inhibition of the heme synthesis path-
way by this metal.
Metals have also made a significant contribution to the
development of the conceptual framework of biomonitoring
(Bernard & Lauwerys, 1997). Some of the basic concepts in
biomonitoring illustrated in Figure 1 largely stem from find-
ings made in populations exposed to metals in the industry or
environment. These studies, initiated in the late 1960s, were
among the first to establish quantitative relationships between
the external exposure, the internal dose, and the early effects.
Actually, heavy metals such as cadmium, lead, or mercury are
among the few pollutants for which these relationships are
sufficiently documented to serve as a basis for biomonitoring
of exposure and effects.
The aim of this article is to illustrate the potential of biomar-
kers for screening toxic effects of metals. I also discuss some
critical issues that need to be considered when assessing the
clinical significance of changes in effect biomarkers and the
public health impact of associations found in population-based
studies.
POTENTIAL OF EFECT BIOMARKERS FOR
POPULATION-BASED STUDIES
Sensitivity
The potential of biomarkers of early effects resides mainly
in their greater sensitivity as compared with classical endpoints
based on symptoms, functional tests, or morbidity data. In the
context of heavy metals, one of the best examples illustrating
the high sensitivity of biomarkers is given by the β2-microglo-
bulin or retinol-binding protein test used in the screening for
cadmium-induced tubular dysfunction. Indeed, a 1% loss of
proximal tubule function is sufficient to increase the urinary
excretion of these proteins by more than 3000%. By comparison,
 1260
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FIG. 1. Relationships between external exposure, internal dose, and early effects permitting the use of biomarkers to assess exposure, effects or susceptibility
to metals (Bernard & Lauwerys, 1986).
serum creatinine, the test used to assess renal function in
clinical practice, rises significantly only when some 40 to
50% of the nephrons are lost. Some biomarkers, however,
are not sensitive enough to be used for monitoring purposes.
This is, for instance, the case of serum prolactin or of uri-
nary homovanillic acid. These two markers of the dopamin-
ergic system show significant changes in industrial workers
with high levels of exposure to neurotoxic metals such as
lead, manganese, or mercury. By contrast, at environmental
exposure levels, these biomarkers show weak or inconsis-
tent associations with metals, meaning that they have a lim-
ited utility for population-based studies (Leite et al., 2002;
de Burbure et al., 2006).
Specificity
The specificity one expects from an effect biomarker is
toward the tissue, the cellular target, or the biochemical path-
way the biomarker is supposed to evaluate. Since effect biom-
arkers are rarely specific for a given metal, it is important to
use them in combination with biomarkers or tests of exposure
for interpreting the data. A diagnosis of metal intoxication can
be made only if the observed adverse effects are associated
with an excessive exposure or body burden of the metal. How-
ever, the lack of specificity of effect biomarkers with respect to
the exposure should not be viewed as a limitation but more as
an advantage. This means, indeed, that the biomarker can be
used to detect toxic effects whatever the nature of the causal
agent. In the case of mixed exposures to metals, which is rather
frequent in the industry or the environment, biomarkers have
thus the potential to integrate the additive or synergistic effects
of the mixture of metals.
A. BERNARD
Noninvasiveness
Noninvasiveness is becoming an increasingly important
issue as biomarkers are increasingly used for monitoring purpose
or as research tools in epidemiological studies. The need for
noninvasive tests is especially important for studies involving
young children. When the examinations have to take place
under field conditions, there is an important risk of participa-
tion bias if one does not have access to noninvasive tests. Nor-
mally, noninvasive biomarkers are those based on excreta such
as urine or exhaled air. Although biomarkers requiring a blood
are in the strictest sense invasive, they can yet be regarded as
noninvasive in comparison with the highly invasive tests
needed for some investigations (e.g., endoscopy, or lung lav-
age techniques for exploring effects in the deep lung). In
exhaled air, one of the most useful effect biomarkers is nitric
oxide (NO), a well-validated marker of airways inflammation.
Although few studies have applied the exhaled NO test to sub-
jects exposed to metals, it is likely that this test could be useful
to assess the pulmonary toxicity of metals (Lund et al., 2000).
Exhaled breath condensate (EBC), a fluid obtained by cooling
exhaled air, also appears a promising tool. EBC contains a
variety of small molecules that could effectively reflect lung
inflammation or oxidative stress as well as the metal doses
retained or stored in the lungs (Goldoni et al., 2004). Such a
biomarker is, for instance, malondialdehyde, which has been
found to increase in workers exposed to a mixture of transition
and hard metals (Goldoni et al., 2004). The assay of lung-
specific proteins in serum (“pneumoproteins”) represents
another interesting approach in the detection of the respiratory
effects of air pollutants, including metals (Bernard & Hermans,
1999). Surfactant-associated proteins A and B in serum can be
used to assess the permeability of the alveolar–capillary
 BIOMARKERS OF METAL TOXICITY IN POPULATION STUDIES
barrier, while serum Clara-cell protein is a sensitive indica-
tor of Clara-cell damage (Halatek et al., 2006). As expected,
tobacco smoking is a major confounder of these lung
biomarkers.
Objective Measures of Outcomes
An aspect that is evident but deserves to be underlined is that
biomarkers, by definition, provide objective measures of out-
comes. In contrast to data collected by questionnaires, they are
thus not prone to recall or memory biases. This might be an impor-
tant issue in some circumstances, in particular when the partici-
pants are not blinded to the tested hypothesis. If the tested
hypothesis is common in the community, the possibility cannot be
excluded that some participants bias their responses to the ques-
tionnaire, depending on their opinion about the studied risks.
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Dose-Response Relationships and Threshold Derivation
The basic principle underlying any toxicological evaluation,
including that based on biomarkers, is that the severity or the prob-
ability of the effect must be related to the dose or exposure level.
Dose-effect/response relationships derived in epidemiological
studies constitute thus an important criterion in the assessment of
the causality. These relationships also allow derivation of thresh-
olds of toxicity, from which safe exposure levels can be recom-
mended. The numerous studies conducted among industrial
workers have shown that metals exert their toxicity in a dose-
dependent manner, with adverse effects occurring usually from a
critical threshold of accumulation in the target organ. Of course, the
thresholds of toxicity vary with the considered endpoint and the
sensitivity of the screening method. For instance, in the case of cad-
mium, tubular dysfunction develops in a strictly dose-dependent
way according to the concentration of the metal in kidney, urine, or
in blood. In industrial workers, depending on the renal biomarker,
thresholds of urinary cadmium above which renal effects are likely
to occur vary from 2 to 10 μg/g creatinine (Roels et al., 2003). The
lowest threshold is associated with an increase in the urinary excre-
tion of some biochemical markers, while the highest threshold cor-
responds to the development of the classical tubular proteinuria.
When these thresholds are exceeded, the likelihood of developing
tubular damage increases almost linearly with the body burden of
the cadmium, as reflected by the urinary concentration of the metal
(Bernard, 2004). Similarly, thresholds of urinary mercury associ-
ated with renal or neurological effects in industrial workers are esti-
mated to range from 30 to 50 μg/g creatinine (Cardenas et al.,
1993). Dose-response relationships for lead-induced toxicity in
workers are also well documented, with a threshold around 300–
400 μg/L for the most sensitive endpoints based on biomarkers.
Predictive Value
Most biomarkers of metal toxicity have no or a low predictive
value. The main reason for this is that they respond at a very early
stage of the intoxication when the progression to the disease can
1261
still be influenced by many factors. In addition, many effect biom-
arkers present too large a variability to have any prognostic value
at the individual level. These biomarkers should thus be used only
on a group basis and mainly for research purpose. There are thus
very few examples of biomarkers of early effects with a docu-
mented predictive value. One example can be found among geno-
toxicity biomarkers with the test of chromosomal aberrations,
which is predictive of a higher cancer risk. Another example is
given by the low-molecular-weight proteins used to screen
cadmium-induced proteinuria. There is now a consensus among
scientists to say that, above a certain level (e.g., 1000 μg/g creati-
nine), an increased urinary excretion of β2-microglobulin or ret-
inol-binding protein is predictive of an faster decline of the
glomerular filtration rate with age (Bernard, 2004).
INTERPRETATION ISSUES
Confounding
Given the number of factors that can affect the function or
integrity of any biological system, confounding is unavoid-
able when using effect biomarkers. Most biomarkers, includ-
ing effect markers, are influenced by gender, age, body mass
index, exercise, and diurnal variation, as well as diseases
unrelated to the exposure (Table 1). Lifestyle factors such as
smoking, alcohol consumption, dietary habits, or behavior
motivated by risk perception can further confound the levels
of biomarkers and modify the shape of dose-response rela-
tionships. As a general rule, confounding is more likely in
epidemiological studies involving adults than in those carried
out on children. Most epidemiological studies using biomark-
ers take care to design their protocol in order to minimize the
influence of potential confounders, and they adjust their
observations for predictors identified by multivariate analy-
ses. When the population size is sufficient, it is also possible
to check for confounding by stratifying the population
according to the level of the confounder and then assessing
associations in groups with no or a low exposure to the con-
founder. An important point also, which has been sometimes
overlooked, is that toxicity thresholds can be reliably esti-
mated only when dose-effect/response relationships have
been established in subjects currently exposed to the metal.
When subjects are removed from exposure, metal concentra-
tions in blood or urine necessarily decrease. If data are not
adjusted for this phenomenon, dose-effect/response relation-
ships are shifted toward lower levels of exposure and the
thresholds of toxicity are underestimated accordingly (Järup
& Elinder, 1994; Bernard & Lauwerys, 1997).
Secondary Associations
Secondary associations can be found when a confounder
unrelated to the metal exposure causes parallel changes in the
effect biomarker and the metal concentrations in biological flu-
ids. Aging, for instance, is accompanied by an increase of the
 1262 A. BERNARD

Issues to Consider When Using Biomarkers to Assess Effects of Metals
Potential of biomarkers
Confounding
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TABLE 1
in Population-Based Studies
More sensitive than clinical endpoints
Specific of the target (organ, tissue, cell, biochemical pathway)
No or low invasiveness (when applicable in urine, exhaled air or serum)
Objective measure (not prone to recall or memory bias)
Derivation of dose-effect/response relationships and toxicity thresholds
Age
Sex (menopauses, multiparity)
Lifestyle (smoking, exercise, diet, drug consumption)
Preexisting diseases (diabetes
Diurnal variation
Intraindividual variation
Instability in the collected matrix
Removal from exposure
Trend in human exposure

Type of association Causative (the metal causes the effect)

Health significance
Reverse causality (the effect increases the internal dose of metal)
Secondary associations (when a third factor unrelated to the metal exposure
influences both the biomarker of effect and the biomarker of exposure)
Type of biological effect (biochemical, structural or functional)
Type of response (adaptative, adverse or hormetic)
Magnitude of changes
Predictive value
Possibility of reversal
Strength of the association
Size of the exposed population

cadmium body burden and an increased proteinuria due to Reverse Causality

the deterioration of the renal function, which may generate
secondary associations due to the dependence of protein
and cadmium excretion on age (Ezaki et al., 2003a;
Moriguchi et al., 2005). Postmenopausal associations
between blood lead and markers of bone metabolism might
be another example of secondary associations due to
menopause-induced changes in bone and lead metabolism
(Akesson et al., 2006). Similarly, the inverse relationship
observed between blood lead and renal function might
reflect the retention of lead in plasma parallel to the age-
related decline in glomerular filtration rate (mechanism of
reverse causality; see later discussion) (Staessen et al.,
1992). Confounding by behavior can also be a source of
secondary associations. Subjects suffering from hyperten-
sion or with a family history of strokes might conceivably
be led to eat more frequently fish in order to increase their
intake of polyunsaturated fat. Doing so, they necessarily
also increase their intake of fish contaminants including
methylmercury, which might give rise to secondary associ-
ations between this pollutant and the risks of strokes or car-
diovascular diseases.
Reverse causality occurs when it is not the metal that increases
the level of biomarker but the opposite. Such a situation can be
met when a functional deficit or a metabolic disturbance, unre-
lated to the metal exposure, increases the concentrations of the
metal in biological fluids. This phenomenon of reverse causal-
ity is a critical issue in epidemiological studies focused on the
renal effects of metals. Since renal excretion is the main route
of elimination of most metals, impairment of renal function
due to another cause than the exposure to the metal (e.g., aging
or some degenerative diseases such as diabetes) should logi-
cally affect the clearance of the metal and thus its concentra-
tions in urine or blood. Theoretically, at least two types of renal
dysfunction are likely to increase the levels of metals biologi-
cal fluids. The first mechanism is a coexcretion of the metal
with urinary proteins. Some metals such as cadmium or mer-
cury circulate in plasma bound to proteins (albumin, metal-
lothionein). These metals must thus follow the same
glomerular filtration–tubular reabsorption pathway as the pro-
teins to which they are bound. An increased urinary excretion
of these proteins caused by a tubular or glomerular dysfunction
unrelated to the metal exposure should thus enhance the uri-
 BIOMARKERS OF METAL TOXICITY IN POPULATION STUDIES 1263

nary output of metals bound to them (Ezaki et al., 2003b). This

coexcretion mechanism, which has been demonstrated in
experimental animals (Bernard & Lauwerys, 1981), might give
rise to noncausal associations between metals and proteins in
urine. The second renal mechanism that might lead to reverse
causality is the retention of metals in plasma when the glomer-
ular filtration rate decreases. This mechanism can operate for
metals such as lead that circulate in plasma free or bound to
small proteins (Staessen et al., 1992). Associations due to
reverse causality might also occur because of the ionic mim-
icry between some toxic metals and some elements such as cal-
cium or iron (Bridges & Zalups, 2005). Disturbances in
calcium homeostasis after menopause or as a result of renal or
bone dysfunction might alter the metabolism of some metals
such as lead or cadmium (Staessen et al., 1999).
Issues of reverse causality are not easy to resolve. One way
is to look at whether associations persist with indicators of
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metal exposure measured in a different matrix. In the case of

renal effects of cadmium, if associations observed with urinary
cadmium also emerge when assessing exposure on the basis of
blood cadmium, this is a strong argument in favor of causality.
By contrast, if they disappear, one should seriously consider
the possibility of noncausal associations due to the coexcretion
of the metal with proteins. Another way is to check for reverse
causality is to examine whether similar associations appear
with non-toxic metals that are also transported by proteins
(e.g., zinc or copper) (Ezaki et al., 2003b).

Toxic, Adaptive, or Hormetic Response

Another important consideration in the interpretation of
changes in effect biomarkers found in epidemiological studies
is that effects detected by the biomarkers are frequently sub-
clinical. In some population-based studies, biomarkers show
deviations that remain in the normal range and have thus no
real meaning at the individual level. Depending on the type of
metal and the studied endpoint, the early response detected by
biomarkers could be purely adaptative and/or reversible. For
instance, the small lead-related renal hyperfiltration children
illustrated in Figure 2 could be the reflection of hemodynamic
changes due to the interference of lead with prostaglandin
metabolism, a phenomenon, which could be transient and
entirely reversible (de Burbure et al., 2006). Similarly, the pre-
clinical tubular effects associated with cadmium and mercury
in populations with low exposures to metals (Hotz et al., 1999;
de Burbure et al., 2006) could also be the manifestation of
reversible proximal tubular alterations. However, when sub-
clinical effects are causally related to toxic metals in children,
they should be interpreted with more caution as one cannot
exclude the possibility that these effects persist and render chil-
dren more sensitive to other stressors later in life.
Another aspect, which has been much debated during recent
years, concerns the shape and models of dose-response rela-
tionships. For decades, toxicologists and epidemiologists
FIG. 2. Renal hyperfiltration induced by environmental lead in children as
reflected by the decreasing serum concentrations of creatinine (CreatS) and
beta2-microglobulin (B2MS) with the increasing concentration of lead in blood.
Data obtained on children aged 8–12 yr recruited in France, Poland, and Czech
Republic. The children have been divided in quartiles of blood lead
concentration (PbB) and the mean values of serum creatinine and beta2-
microglobulin have been calculated after standardization for other cofactors.
Variables preceded by R are ranked variables. Statistically significant difference
with first quartile: *p < .05; **p < .01; ***p < .001. (de Burbure et al., 2006).
investigating the effects of metals have relied for their analyses
on the assumption that dose-response relationships can be only
monotonous, i.e., that the response must necessarily go in the
same direction as the dose. Different models have been devel-
oped to account for deviations from linearity and the existence
of thresholds. Since a few years ago, this dogma is being chal-
lenged by the concept of hormesis that is now receiving
increasing attention (Cook & Calabrese, 2006). The hormetic
concept can be defined as low-dose stimulation and high-dose
inhibition (Cook & Calabrese, 2006). Hormesis is a phenome-
non by which dose-response relationships are characterized by
low-dose stimulation and high-dose inhibition resulting in an
 1264 A. BERNARD
inverted U-shaped or a J-shaped dose-response. This concept is
increasingly invoked in experimental studies when a biphasic
response to metals is observed (Coeurdassier et al., 2005;
Hunter et al., 2004). The renal hyperfiltration observed in chil-
dren with low environmental exposure to lead (Figure 2) might
be an example of a hormetic effect, since this metal is a well-
known nephrotoxin that decreases renal function at high doses
(de Burbure et al., 2006).
Health Significance and Public Health Implications
Assessing the health significance of associations between
effect biomarkers and metal exposure is a delicate task that
implies taking into consideration several issues. The first issue
to consider is the type and magnitude of changes in the effect
biomarker. Some biomarkers, such as urinary protein excre-
tion, can show variations of several orders of magnitude. In
that case, an increase by a factor of 2 or 3 has certainly not the
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same meaning as an increase by a factor of 100 or more. For
instance, a moderate increase in the urinary excretion of ret-
inol-binding protein can be partly reversible, while an increase
by a factor of more than 100 is definitively irreversible and
associated with a loss of the renal function (Table 2). The
health significance is probably also different according to the
type of change (e.g., biochemical or functional, adaptative or
toxic) and the mechanism of toxicity. In that respect, it might
be appropriate to distinguish changes caused by a long-lasting
accumulation of the metal from changes due to recent expo-
sures, which might be reversible. When translating associa-
tions between effect biomarkers and metal exposure in terms of
public health impact, several other issues must be considered,
among which the most important ones are the strength of the
association and the size of the population at risk. Even if
TABLE 2
Significance of Increased Values of β2-Microglobulin (β2-m)
and Retinol Binding Protein (RBP) in Urine (Bernard, 2004)
β2-m or RBP in urine
(μg/g creatinine) Significance
<300 Normal value
300–1000 Incipient cadmium-induced tubular
dysfunction(possibility of
reversibility if cadmium exposure
is not too high)
1000–10,000 Irreversible tubular proteinuria
likely to accelerate the decline of
glomerular filtration rate (GFR)
with age. At this stage, the GFR is
normal or slightly impaired
>10,000 Overt cadmium nephropathy usually
associated with a decreased GFR
causative relationships between metal exposure and adverse
effects are weak, they might still suggest a significant burden
of diseases if a large number of people are concerned. Simi-
larly, the effects probably do not have the same meaning if
they are observed in young children or in the elderly. The trend
in human exposure is also a point to bear in mind. Human
exposure to some persistent pollutants including some metals
(e.g., lead) has declined during the last decades. Therefore,
adverse effects linked to these metals and evidenced now in
adults or adolescents might be the consequence of much higher
exposures in the past and thus not be an accurate reflection of
the current exposure levels.
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