Toxicology of Industrial Compounds

– An uncertainty factor for time extrapolation (subchronic to chronic
exposure) was also not applied, since the red blood cell haemolysis was
regarded as a transient phenomenon observed predominantly on the
first few days of exposure thus indicating that longer exposure would
not have resulted in a lower rat NOAEL.
– Although there is some uncertainty about the actual magnitude of the
contribution of dermal uptake to the total uptake during BE vapour
exposure, ECETOC concluded that even under worst-case conditions
the BAA concentrations achieved are not sufficient to cause haemolysis
in man and there is no need for the adjustment of the predicted human
NOAEL for route.
In conclusion, an occupational exposure limit of 20 ppm (8 h TWA) was
recommended, also taking into account all other effects that may be
associated with BE-exposure. This value is similar to the rat NOAEL of 25
ppm for the most sensitive parameter, i.e. haemolysis, and was derived
using scientific data instead of applying default factors to the rat NOAEL,
a procedure which would have overpredicted the human risk associated
with BE-exposure.
Conclusion
N.FEDTKE 175
The use of PBPK models and mechanistic data in risk assessment tends to
reduce the uncertainties in comparison with default methodologies by
replacing the administered dose with the delivered dose and also tends to
reveal uncertainties concealed in default methodologies (Wilson and Cox,
1993). However, there are also limitations in the development of PBPK
models. One limitation is that the mechanism of the toxic effect has to be
known, otherwise the replacement of the external dose by internal dose
surrogates is not possible. In addition, extensive validation of the model is
necessary in order to replace default approaches in risk assessment. For the
time being, the development of PBPK models appears to be restricted to
high production chemicals where the existing data base allows
identification of an accepted mechanism of toxic action and validation of
the model. Concern has been expressed that the use of point estimates in
PBPK modelling instead of ranges of biologically plausible values leads to
an increase in the uncertainty (Portier and Kaplan, 1989). However, a
recent study from the Delivered Dose Work Group of the American
Industrial Health Council came to the conclusion that incorporation of
‘pharmacokinetic information in a risk assessment,…, leads to both a more
accurate estimate of risk and a better specification of the true uncertainty’
(Wilson and Cox, 1993). A detailed discussion of the sources of
uncertainties is also provided in this reference.