Toxicology of Industrial Compounds

172 EXTRAPOLATION OF TOXICITY DATA AND ASSESSMENT OF RISK
depletion in hepatic and extrahepatic tissues (D’Souza et al., 1988;
Frederick et al., 1992; Krishnan et al., 1992), kinetic interactions of parent
compounds in mixed exposures (Tardif et al., 1993) or the amount of
adducts formed by macromolecular binding (Krishnan et al., 1992) are
predictions that may also be generated by PBPK modeling. As a result of
the simulations, quantitative information on the internal dose of a
chemical or its metabolites in the target tissue is obtained and can replace
the administered dose conventionally used in risk assessment. After
validation of the PBPK models in experimental animals, human PBPK
models can be developed either by allometric scaling of the physiological
and biochemical parameters or preferably using the actual human
parameters. Following the prediction of the target tissue dosimetry in
humans, the appropriate dose surrogates are related to the effect of interest
and quantitative species differences are determined. This information
provides the possibility to base the species extrapolation on scientific data
instead of on arbitrarily assigned default factors and as a consequence the
uncertainty of the extrapolation procedures applied in conventional risk
assessment may be reduced.
Description and use of the PBPK model for 2butoxyethanol
2-Butoxyethanol (BE) is a widely produced glycol ether used as a key
ingredient in water- or solvent-based coatings, industrial and consumer
cleaning products, and as solvent in a variety of products. Haemolysis was
identified as most sensitive indicator of BE-induced toxicity in several
species of laboratory animals and has received the most attention as a
critical effect for human risk assessment (ECETOC, 1985, 1994). The
experimentally determined subchronic NOAEL for the rat is 25 ppm. The
major metabolite of BE is 2-butoxyacetic acid (BAA) which has been
identified as the metabolite responsible for the haemolysis of red blood
cells in in vitro and in vivo studies (Bartnik et al., 1987; Ghanayem et al.,
1987; Ghanayem, 1989). Changes in the deformability of rat erythrocytes
appear to precede haemolysis upon treatment with BAA. Treatment of
human erythrocytes with BAA did not induce changes in deformability
(Udden and Patton, 1994; Udden, 1994). The observed species differences
may be due to differences in the lipid composition of erythrocyte
membranes, differences in membrane proteins associated with anion
transport processes, or differences in the erythrocyte cytoskeleton (Udden,
1994; Udden and Patton, 1994). Humans are most likely to be exposed to
BE by the dermal or inhalation routes due to the widespread use of BE in
cleaning products. Assessment of the risk resulting from BE use has to
account for these routes of exposure and the formation of BAA as the
active metabolite. In order to assist in the risk assessment, PBPK models