Toxicology of Industrial Compounds

368 CONTROVERSIAL ISSUES IN SAFETY ASSESSMENT
general population. Thus, AFs of >1000 should always be questioned
as possibly over-conservative for threshold effects, since exposure
levels thereby obtained could also be acceptable for non-threshold
effects like carcinogenicity. The assumptions underlying such high AFs
should be re-examined critically.
In the light of these considerations AFs for a developmental toxicity of
1000– 5000, as they are under discussion by some groups today, should
also be questioned as possibly being over-conservative. It should not only be
taken into account that developmental effects most often will have
thresholds but also that their severities span a wide range from slight foetal
weight impairment up to disabling malformations.
In addition an unreflected selection of default factors in ‘classical’ organ
toxicity can easily lead to over-conservative AFs: starting with a factor of
10 each for inter- and intra-species variability yields the AF of 100 used for
ADI-calculations. In addition the following default factors are sometimes
proposed:
– Extrapolation from subacute/subchronic exposure to chronic exposure:
a default factor of 10.
– Extrapolation to the NOEL, if only a LOEL was obtained: a default
factor of 2–5.
– Taking into account an inappropriate experimental design: a default
factor of 2–5–10.
Thereby, for a multiple dose study with a marginal effect at the lowest dose
level and an experimental design not fully in accordance with today’s
standards, these default factors would result in a final assessment factor of
4000– 50000. It is highly questionable whether such an AF is really
appropriate for threshold effects in comparison to the example given above
for carcinogenicity.
Non-threshold effects
Other principles and approaches for classification and risk assessment have
to be applied for non-threshold effects since safe exposure levels cannot be
defined at which an adverse health effect will definitely not occur. Thus,
for these compounds carcinogenic and mutagenic effects cannot be
excluded even at very low dose levels albeit with extremely low
probability.