Toxicology of Industrial Compounds

228 PEROXISOME PROLIFERATION
Species differences in response
Many studies have examined species differences in hepatic peroxisome
proliferation (Cohen and Grasso, 1981; Rodricks and Turnbull, 1987;
Stott, 1988; Lock et al., 1989; Moody et al., 1991; Bentley et al., 1993).
Based on both marker enzyme activities and ultrastructural examination
the rat and mouse are clearly responsive species, the Syrian hamster
appears to exhibit an intermediate response, whereas in most studies the
guinea pig is either nonresponsive or refractory. For example, DEHP
readily produces peroxisome proliferation in the rat and mouse, to a lesser
extent in the Syrian hamster but not in the guinea pig (Osumi and
Hashimoto, 1978; Lake et al., 1984b). Similar results have been obtained
with more potent compounds including ciprofibrate, clobuzarit, LY
171883 and nafenopin (Orton et al., 1984; Eacho et al., 1986; Lake et al.,
1989; Makowska et al., 1992).
When assessing species differences in response a number of factors
should be considered. These include the metabolism, disposition and dose
of the test compound, sex differences, as well as intrahepatic differences in
response. The importance of metabolism is illustrated by the industrial
solvent trichloroethylene which produces peroxisome proliferation and
liver tumours in the mouse but not in the rat (NCI, 1976; Elcombe, 1985).
Metabolic studies demonstrated that the trichloroethylene was extensively
metabolised to trichloroacetic acid in the mouse, whereas this was a minor
saturable route of metabolism in the rat. That the difference in
trichloroacetic acid formation was responsible for the observed species
difference was demonstrated by the fact that this compound produced
peroxisome proliferation in rat and mouse hepatocytes both in vivo and in
vitro (Elcombe, 1985). An example of compound disposition is provided
by DEHP which is known to be more extensively absorbed after oral
administration in the rat than in the marmoset (Rhodes et al., 1986).
However, the observed in vivo species differences in response are supported
by the observation that metabolites of DEHP which produce peroxisome
proliferation in rat hepatocytes in vitro have no significant effect in
cultured marmoset hepatocytes (Elcombe and Mitchell, 1986). Generally,
in vitro studies with primary hepatocyte cultures from the rat, mouse,
Syrian hamster, guinea pig and marmoset have supported the results of in
vivo studies in these species (Elcombe 1985; Elcombe and Mitchell, 1986;
Lake et al., 1986; Bieri, 1993; Bentley et al., 1993; Foxworthy and Eacho,
1994).
Several studies have examined the ability of rodent peroxisome
proliferators to produce effects in primates and humans. With respect to
primates, studies with a number of compounds in both New (e.g.
marmoset) and Old (e.g. Rhesus monkey) World monkeys have failed to
provide any evidence of significant hepatic peroxisome proliferation