Toxicology of Industrial Compounds

N.FEDTKE 173
were developed that describe the uptake, metabolism and disposition of BE
and BAA (Johanson, 1986; Corley et al., 1993, 1994; Shyr et al., 1993).
The model of Corley et al. (1993, 1994) is a refinement of Johanson’s
model (1986) and consists of two submodels. The first submodel describes
the uptake and disposition of BE and consists of the tissue compartments
rapidly perfused organs, slowly perfused organs, fat, skin, muscle,
gastrointestinal tract, and liver as the metabolizing tissue. The BE
submodel allows uptake via the inhalation and dermal routes and in
addition provides the possibility of uptake via IV infusion and the
gastrointestinal tract in order to validate the model with laboratory data.
The second submodel tracks the disposition of BAA in the same tissue
compartments, but the kidney was removed from the rapidly perfused
organs as separate tissue to allow for the excretion of BAA metabolites.
The two submodels are linked together by the metabolism of BE to BAA
via a saturable enzymatic pathway catalyzed by alcohol and aldehyde
dehydrogenases in the liver. Competing pathways (BE conjugation and
BE O-dealkylation) are lumped together and described by an additional
enzymatic pathway with Michaelis-Menten kinetics. The model assumes
that BAA is bound to proteins in blood and is eliminated by a saturable
process in the kidneys. The rate of BAA elimination by the kidneys is
described as the sum of glomerular filtration rate of BAA and the acid
transport of BAA assuming that no reabsorption occurs. The biochemical
constants determined experimentally in the rat were scaled to humans by
(body weight) 0.7 . In the validation process, the model successfully described
a wide variety of rat and human data from different laboratories using
several routes of administration.
BAA was predicted to be formed more rapidly in rats compared with
humans, but to be eliminated slower in humans than in rats. In summary,
higher maximum concentrations of BAA in blood (C max) and also higher
areas under the BAA concentration-time curves (AUC) were predicted for
rats than for humans, especially as the vapour concentration was
increased. For the purpose of dose-response and interspecies extrapolation,
BAA-C max and BAA-AUC were used as estimates of the internal dose
surrogate; C max can be related directly to the in vitro haemolysis studies
with BAA and is responsive to the dose-rate. The in vitro studies performed
(Bartnik et al., 1987; Ghanayem et al., 1987; Ghanayem, 1989; Udden,
1994; Udden and Patton, 1994) suggest that approximately 0.2 mM BAA
is required to produce slight haemolysis of rat red blood cells. At about 2
mM BAA nearly complete haemolysis was observed. The model predicts
for nose-only exposure that these concentrations are reached in the rat at
BE exposure concentrations of about 100 ppm and 800 ppm for 6 h,
respectively, which is consistent with observations in vivo (Tyler, 1984;
Sabourin et al., 1992).