Chemistry Reference
In-Depth Information
biological monitoring (BM), and response. External
exposure can be measured by environmental moni-
toring as the concentration of a metal compound in
air or food. The dose or intake per day can be esti-
mated from the measured concentrations and esti-
mated daily ventilation volume (inhaled dose) or
amount of food consumed (oral dose or oral intake).
A proportion of an oral or inhaled dose is taken up
in the body, initially to blood. Metal concentration in
blood, if monitored, is an
exposure biomarker of inter-
nal dose
. The proportion of the external dose absorbed
into the body can be derived, and such information
is an important aspect of the toxicokinetic or meta-
bolic model of the metal compound in question and
impacts on the adverse effects induced. Another
important component of the toxicokinetic model
describes the relationship between levels in indica-
tor media (biomarkers), such as blood and urine, and
accumulation (dose) of the metal in critical organs.
The latter is closely related to the target dose. Accu-
mulation of metals in critical organs can sometimes
be monitored by external measurements such as Cd in
kidney by
in vivo
neutron activation, thus providing
an exposure biomarker, indicating concentration in critical
organ
. For effects occurring in internal organs, direct
measurements of the interaction between the metal
and target molecules are seldom possible. However, in
some instances, there is a close relationship between
effects in blood and in critical organs. An example is
the interaction between lead and enzymes in the bone
marrow, which can be monitored by measurements
in blood, and they can, thus, be a useful biomarker of
target dose. In some instances, it may be possible to
use DNA adducts in blood cells as a biomarker of tar-
get dose causing carcinogenic effects in body organs.
However, documentation of such relationships for
metallic compounds is limited at present and may
only be applicable for a few metal compounds, as
pointed out in the Chapter 5.
In some instances, it may be possible to defi ne popu-
lation subgroups with particular sensitivity by studying
polymorphism in enzymes and membrane molecules
as
biomarkers of susceptibility
. However, actual examples
of successful application of biomarkers of susceptibility
in risk assessment of metal exposure so far are limited.
Variation in binding of metals to sequestering proteins
before interaction with target molecules may also form
a basis for classifying subpopulations into susceptible
and less susceptible groups. The observations of such a
relationship using metallothionein gene expression in
peripheral blood lymphocytes as a biomarker of renal
susceptibility to damage caused by cadmium (Lu
et al.
,
2001) are interesting but need to be confi rmed, refi ned,
and developed.
Some examples of useful
biomarkers of early (critical)
effects follow:
The detection of early damage to the kid-
ney tubules by cadmium using urinary levels of low
molecular weight proteins such as beta
2
-microglobulin,
protein HC, and the enzyme
N
- acetylglucosaminidase.
Biomarkers of disease
are monitoring markers used
clinically in the diagnosis of disease. In the case of
cadmium, damage to the kidney, excessive excretion
of beta
2
-microglobulin (>1 mg/g Crea), or decreased
tubular reabsorption of phosphate are such markers
for tubular damage.
In biological monitoring of toxic metals, knowledge
about the toxicokinetics of the compound is of crucial
importance. Because many metals display differenti-
ated and specifi c patterns of disposition among tissues
in the human body, and for several metals adequate
knowledge is available on toxicokinetics and meta-
bolic models, this situation can be seen as a special
aspect of metal biomonitoring. Other aspects are that
it has been possible for a long time to perform rela-
tively precise determinations of metals in biological
indicator media at a reasonable cost. The database and
experience of biological monitoring of metals thus is
considerable. However, the data are focused on a lim-
ited number of metals, whereas data on other metals
are still incomplete or even lacking.
For cadmium and lead, biomarkers of effect have
been available for a long time, and they are reasonably
well validated. This effect of cadmium, renal tubular
damage, is considered a critical effect.
1
However, in
the case of lead, adverse effects on the central nerv-
ous system, notably in children, are considered to be
the critical effect, and it is not known how closely the
hematological effects of lead are related to the neuro-
toxicological effects. At present, available biomarkers
of nonthreshold effect or target dose have not been val-
idated and cannot be widely used or recommended for
routine assessments. Considerable efforts are needed in
validating recently developed effect and susceptibility
biomarkers (Albertini
et al.
, 2000; IPCS, 2001).
2 SOURCES OF PREANALYTICAL
AND ANALYTICAL ERROR
A number of errors may occur before the chemical
analysis of the substance of interest, and analytical
errors may also occur in the chemical analysis. When
using exposure biomarkers in the classical sense of
biological monitoring (i.e., analyses of metals in blood,
1
For a discussion of critical effects in occupational and environ-
mental health see Nordberg (1976), and Chapter 14.
