Toxicology of Industrial Compounds

N.P.E.VERMEULEN ET AL. 31
nephrocarcinogenicity in the male rat is dose-dependent. More specifically,
cytotoxic kidney damage is a feature of high continuous exposure to TRI
over prolonged periods of time. This is unlikely to occur in humans during
occupational exposure. In fact, TRI has been found not to be nephrotoxic
in humans chronically exposed to low levels of TRI (50 mg m −3 ).
Consequently, it is unlikely that the renal tumors which are seen in rats at
nephrotoxic dose levels of TRI and which are related to β-lyase mediated
bioactivation of 1,2-DCV-Cys, are relevant to human health hazards at
reasonably foreseeable levels of exposure.
Physiologically based toxicokinetic modeling of 1,3butadiene
Physiologically based pharmaco(toxico)-kinetic models differ from the
conventional compartmental models in that they are based to a large extent
on the actual physiology of the organism. Instead of compartments defined
largely by the experimental data themselves, actual organ and tissue groups
are used with weights and blood flows from the literature (Bischof and
Brown, 1966). Instead of composite rate constants determined by fitting
the actual experimental data, physical-chemical and biochemical constants
of the compound are used. The result is a mode which predicts the
qualitative behavior of the experimental time course without being based
on it. Refinements of the model to incorporate additional insights gained
from comparison with experimental data yields a model which can be used
for quantitative extrapolations well beyond the range of experiments. In
recent years several PBTK- and PBPK-models have been published: for
methylene chloride, see Andersen et al., 1987; for a review see Leung et al.,
1988; for 1,3-butadiene, see Evelo et al., 1993.
The development of a PBTK/PBPK model can be divided into a number
of steps: (a) inventory of physiological and toxicological behaviour of the
compound, (b) mathematical description of the biochemical/(patho)
physiological processes involved, (c) parameterization of the mathematical
descriptions, (d) the construction of the model, (e) refinement and
validation of the model and (f) use of the predictions and risk assessment.
As an illustrative example of this approach the recently described PBTKmodeling
of 1,3-butadiene disposition and toxicity might be used (Evelo et
al., 1993). 1,3-Butadiene used for the production of styrene-butadiene
rubber, is known amongst others to cause lung carcinogenicity. In the rat
the carcinogenicity of 1,3-butadiene is less pronounced while the evidence
for human carcinogenicity is inconclusive, Monoand di-epoxy-butadiene
are reactive metabolites held responsible for this effect. Butadiene
monoxide is formed by microsomal fractions of the lung and liver of several