Toxicology of Industrial Compounds

370 CONTROVERSIAL ISSUES IN SAFETY ASSESSMENT
which can be used by industry to tailor experiments in order to refute the
classification of a questionable animal carcinogen. In the long run there
will be no benefit if about 50 per cent of all chemicals are classified as
carcinogens, neither for the public nor for industry nor for an adequate
protection of human health.
Risk assessment
Most scientific committees and regulatory agencies refrain from
scientifically based risk assessments for carcinogens but rather propagate
an exposure as low as possible. And if a risk assessment is really carried
out, it usually just applies a simplistic mathematical extrapolation using the
linearized multistage model and highly conservative default assumptions to
bridge data gaps. These mathematical procedures arrive at a scientifically
unjustified numerical precision of the risk estimate. One of the problems is
to explain to the public the real meaning and the uncertainties of such a
risk assessment. A possible alternative could be to substitute the
mathematical extrapolation by an appropriate assessment factor which of
course has to take into account the severity and irreversibility of the
carcinogenic effect. The simplistic mathematical modelling might be used
only for selection of priority chemicals for further in-depth investigations.
On the other hand, a mathematical risk assessment can be an
appropriate procedure for chemicals with a broad experimental data base,
when the most relevant default assumptions are substituted by real data.
This would be of primary importance for:
– the selection of the mathematical model: the simplistic linearized
multistage model presently in use could be substituted by biologically
driven models, like that proposed by Sielken (1989) or the MVK-model
(Moolgavkar and Knudson, 1981; Moolgavkar et al., 1988).
– dose scaling from animals to humans: presently the experimental dose in
mg kg −1 body weight is often extrapolated to humans by transforming
the dose to mg m −2 body surface. This is used both for compounds
which are metabolically toxified and detoxified, the scientific basis for
such an undifferentiated procedure is at best highly doubtful. In the
future this default assumption could be substituted by physiologically
based pharmacokinetic (PBPK) modelling.
– estimation of the target dose: presently the external dose to which the
animals are exposed is considered to be proportional to the dose
reaching the target tissue or the target chemical entities—generally the
DNA. Again in future this could be substituted by adequate PBPK
modelling.