Toxicology of Industrial Compounds

N.FEDTKE 169
– extrapolation of effects from one route of exposure to another route,
and
– extrapolation of effects observed in a rather homogeneous animal
population to a heterogeneous human population (interspecies
extrapolation), which also has to take into account the existence of
subgroups regarded as more sensitive as the rest of the population
(intraspecies extrapolation).
Essential for all procedures used in health risk assessment is the
determination of the so-called critical effect. The critical effect may be
defined as the adverse effect judged to be most appropriate as the basis for
the risk assessment. Hence, the first step is the review of all available data
on a chemical and the assessment of the adequacy of the database for the
determination of the critical effect. On the basis of the critical effect,
toxicants may be divided into two classes characterized by:
– a threshold of response, i.e. the adverse effect on health is not expressed
until the chemical, or the ultimately toxic metabolite, reaches a
threshold dose or dose rate in the target tissue, or
– no threshold of response, i.e. there is no threshold exposure level below
which effects will not be expressed. This implies that there is some risk at
any level of exposure. Examples are genotoxic carcinogens or germ cell
mutagens.
Based on these classes two general approaches to health risk assessment
have been used.
The first approach involves the use of ‘safety factors’ applied to the
NOAEL or the lowest-observed-adverse-effect level (LOAEL) of a
threshold effect determined in experimental animals (safety factors are
recently referred to as ‘uncertainty’ or ‘assessment’ factors). The magnitude
of the uncertainty factors varies between the regulatory bodies that are
concerned with risk assessment, but usually they take into account the
interspecies extrapolation (default factor 10) and intraspecies extrapolation
(default factor 10). The magnitude of the default factors appears to be
based more on the conventional use of the decimal system than on
scientific reasons and have been proposed first by Lehman and Fitzhugh
(1954) for the derivation of acceptable daily intakes (ADIs) for food
additives. Additional uncertainty factors may be used for extrapolation to
chronic exposure from subacute or subchronic exposure, adequacy of the
database, extrapolation of a LOAEL to a NOAEL and severity of effects.
The resulting overall uncertainty factor often reaches values of 1000 or
higher, which is an indication of the imprecision of the derived tolerable
intake. Refined extrapolation procedures using subdivisions of the default