Risk Assessment - Toxicology of Metals - page 286

The use of probabilistic risk assessment approaches to
take into account variability within exposed populations
is a further refi nement to these statistical methods.
The BMD, as discussed in the foregoing text, is a
point on the dose scale in a dose-response relationship
(using so-called quantal data), and the concept has
been most frequently used for such data. The advan-
tages of converting dose-effect data (continuous data)
to dose-response data have been discussed in Chapter
6. The advantage can be that the occurrence of values
considered “abnormal” from a clinical chemistry point
of view can be used—usually deviating by more than
two times the standard deviation from the mean among
healthy persons. When such specifi c values are known
to be related to adverse long-term health outcomes, as
for low mol proteinuria in population groups exposed
to cadmium (see Chapter 23), the BMD and BMDL are
meaningful points in the dose scale that can be used
for risk assessment.
The benchmark approach has been extended so that
it can be used with dose-effect data (continuous data),
also those obtained in epidemiological studies, where
confounder adjustment is needed (Budtz-Jorgensen
et al ., 2001; Crump, 1995; Kalliomaa et al ., 1998). Such
benchmark dose calculations may be useful in risk
assessments, but their implications in terms of health
risk usually have not been defi ned or discussed. The
infl uence of statistical variance in such calculations has
been considered by Sand et al . (2003).
When using BMD values in risk assessments, it is
important to specify whether dose-response (quan-
tal or dichotomous) data or dose-effect data (con-
tinuous data) are used. The BMR should always be
specifi ed for dose-response data. It is also important
to describe what methods are used to defi ne the
magnitude of effect that is under consideration when
using dose-effect data. In line with the terminology
of this topic, the term BME (benchmark effect) is rec-
ommended for dose-effect data but has not yet been
used as far as known by us.
Measurement imprecision in the dose scale (e.g., in
epidemiological studies) will also affect the BMD and
should be dealt with as discussed in Chapter 8.
If the considerations discussed in this section are
taken into account, BMD/LBMD calculations pro-
vide very useful numbers for risk assessment and are
recommended when adequate data allowing such
calculations are available.

on Metal Toxicity, 1976). The dose-response relation-
ship expressing the response of a particular effect as
a function of metal concentration in the critical organ
thus displays the frequency distribution of individual
critical concentrations.
It is not possible to speak of one single critical
concentration even for a specifi ed effect. Because this
had sometimes been done, Friberg and Kjellstrom
(1981) suggested the introduction of a “population
critical concentration” (PCC) instead of a “critical con-
centration” when assessing data based on a population.
To the PCC should be appended a number indicating
the response rate expected at this PCC. PCC-50 would
be the concentration in the critical organ at which
50% of a population has the critical effect, PCC-20 the
concentration at which 20% has the critical effect, and
thus has exceeded their individual critical concentra-
tions. The PCC would bring together a number of
previously used terms, such as “earliest effect level,”
“no-observed-adverse effect level” (NOAEL), “critical
concentration,” without further specifi cation. The use
of the PCC concept would be similar to the use of LD50
and ED50 in toxicology and is similar to the benchmark
dose concept (see Section 4.1.3).
In risk assessment and risk control of chemicals with
specifi c responses, it is a separate decision to decide on
a maximum acceptable response rate for a given effect
based on a risk estimation. If 5% is the maximum, then
the PCC-5 has to be established. If 0.1% is the maxi-
mum, then a PCC-0.l must be established. Standards
refer to exposure, however, and it is, therefore, nec-
essary to defi ne the exposure that gives rise to 5%
response. To arrive at this exposure, interindividual
parameters have to be taken into consideration. Varia-
tions in metabolism and sensitivity to a toxic substance
will be parameters of importance for the individual.
For example, it should be established whether high
absorption, unfavorable interactions with other sub-
stances, high retention, and low excretion together
with high tissue sensitivity within the critical organ
may favor an effect even at low exposure levels.
To predict the proportion of a population that has
concentrations in the critical organ above the indi-
viduals' critical concentrations, knowledge of the
distribution of the concentrations of the substance
in the critical organ on a population basis is needed
together with data on the PCCs. This will give, on the
one hand, data on the combined effect of the exposure
and metabolism on tissue concentrations, and, on the
other hand, information on PCCs. The proportion of
a population with concentrations above the critical
concentration is then equal to the probability of any
individual in the population having an actual concen-
tration in the critical organ above his or her critical con-

4.1.4 The Critical Concentration on a
Population Basis

The critical concentration is established on an indi-
vidual basis and varies among individuals (Task Group