Toxicology of Industrial Compounds

N.P.E.VERMEULEN ET AL. 29
Figure 2.10 Oxidative metabolism of TRI in the rodent and mammalian liver and
the formation of metabolites which are excreted in the urine.
concentration in the former species. The relevance of the mechanisms of
liver tumor formation in B 6C 3F 1 and Swiss mice for humans exposed to
TRI has been assessed in studies comparing metabolic rates in mice, rats
and humans. In contrast to the rat, the oxidative metabolism of TRI to
TCA in humans is not limited by saturation. In this respect, humans
resemble the mouse and might be able to produce sufficient TCA to induce
peroxisome proliferation and consequently liver cancer. However, there are
significant differences between mice and humans. First, humans metabolize
approximately 60 times less TRI on a body weight basis than mice at
similar exposure levels. Second, TCA has been shown to induce
peroxisome proliferation in mouse hepatocytes but not in human
hepatocytes (Table 2.3). Consequently, the combination of extensive
oxidative metabolism of TRI to TCA and the ability of TCA to induce
peroxisome proliferation appear to be unique to B 6C 3F 1 and Swiss mice.
TRI-induced renal toxicity and tumors were found in Sprague-Dawley,
Fischer 344 and Osborne-Mendel rats. These nephrocarcinogenic effects of
TRI were specific to male rats and were not seen in female rats nor in mice
of either sex. 1,2-DCV-Cys, formed from TRI via the mercapturic acid
pathway, has been identified as a likely metabolite involved in the observed
renal toxicity and probably also in renal carcinogenicity in rats. TRI is
metabolized by a minor pathway involving initial hepatic GSH-conjugation
of TRI. The resulting DCV-G is further metabolized (Figure 2.11) and
excreted in urine as two regioisomeric mercapturic acids, namely vicinal 1,
2-DCV-Nac and geminal 2,2-DCV-Nac (Figure 2.11). 1,2-DCV-Cys (the
precursors of 1,2-DCV-Nac) is a substrate for the renal L-cysteine S-