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Setting upper levels for nutrient risk assessment
of uncertainty factor should be based on the available
scientific evidence [7].
Commonly the NOAEL is divided by a default
uncertainty factor of 100 to derive a guidance value.
This default value comprises two factors of 10: one for
interspecies differences, covering extrapolation of data
from animal models to humans, and one for interindividual
differences (human variability). Uncertainty
factors are illustrated in table 2.
As a further refinement, the International Programme
on Chemical Safety (IPCS) framework [7, 9]
apportions the default uncertainty factor [10] for interspecies
differences between two factors of 2.5 and 4.0
for toxicodynamics and toxicokinetics, respectively,
and that for intraspecies variability into 3.2 and 3.2 for
both components. These values represent an initiative
to use chemical-specific adjustment factors derived
from kinetic and dynamic data to derive expressions of
uncertainty that are more definitive and specific than
are default values for uncertainty factors.
Sometimes additional factors are used to compensate
for the absence of data, such as an inadequate
long-term (chronic) study, no discernible NOAEL and
the need to use a LOAEL, other gaps in the data, and,
sometimes, the severity of the adverse effect.
The preceding outline is the ideal. It describes the
application of the NOAEL approach to a systematic
set of data. There is usually some such structure in the
data for additives that facilitates the use of uncertainty
factors, but for contaminants the quality of the data
makes their use more challenging, and often several
uncertainty factors are applied, resulting in a relatively
high overall factor.
TABLE 2. Typical uncertainty factors used in toxicology
Other approaches to uncertainty and improving
risk assessment
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The NOAEL approach has been criticized because
it may not use all the available data, including dose–
response data, and because the dose–response curves
are customarily derived by using large, e.g., 10-fold,
incremental steps in the intakes of the chemicals
under study. Furthermore, the NOAEL approach is
deterministic and does not readily allow for flexibility
in selecting different levels of risk. There are alternative
approaches to hazard characterization, and two, in particular,
are seen as being potentially useful. These are
the benchmark dose–response and categorical regression.
Both allow for more extensive use of available
information and for calculation of levels of exposure
that can be associated with predetermined levels of
risk (e.g., 1%, 2.5%, 5%) within the population. These
will be described briefly. Better descriptions of their
use and applicability are in the references cited from
which I have derived this commentary.
Benchmark dose modeling
Benchmark dose (BMD) modeling [2, 11, 12] fits a
dose–response regression to more of the available
dose–response data acquired from animal models and
human studies (fig. 1). This provides an overall estimate
of the variance and a way of estimating dose levels
at which specific proportions of the population under
study would experience an event or effect over and
above the base occurrence. A statistical lower bound
(BMDL or LBMD) customarily set at 95% is used.
The statistical lower confidence limit of the lower
bound is generally used for developing an RfD [12].
Thus, this approach uses all the dose–response data to
find the dose associated with a predefined response,
whereas the NOAEL usually derives from a single
Uncertainty factor Use Value
Intraspecies (intrahuman) When extrapolating long-term studies to provide acceptable
daily intakes or short-term studies to produce acute
reference doses in the same species
Interspecies When extrapolating, from one species to another, longterm
studies to provide acceptable daily intakes or shortterm
studies to produce acute reference doses
Subchronic to chronic Where no adequate chronic study is available Up to 10
LOAEL to NOAEL If the critical effect in the critical study is a LOAEL Up to 10 (often 3 based
on dose spacing)
Incomplete database Where the standard data package is not complete Up to 10
Steep dose–response curve Where the dose–response curve for a compound is steep,
a small error in extrapolation would have dramatic consequences
NOAEL, no observed adverse effect level; LOAEL, lowest observed adverse effect level
10
10
Judgment, 3–10