Toxicology of Industrial Compounds

B.G.LAKE AND R.J.PRICE 227
hepatic DNA (Reddy and Rao, 1989; Bentley et al., 1993; Lake, 1993).
However, the available data suggest that sustained oxidative stress is
unlikely to be solely responsible for per oxisome proliferator-induced
hepatocarcinogenesis in rodents. Although evidence of oxidative damage to
hepatocytes has been observed in some studies, the magnitude of such
effects does not correlate with the potency of the compound to produce
tumours. For example, oxygen radical attack on DNA is known to result in
a variety of modified DNA bases including 8-hydroxydeoxyguanosine.
However, at bioassay dose levels both DEHP and DEHA produce similar
increases in hepatic 8-hydroxydeoxyguanosine levels, but only DEHP
produced liver tumours in male F344 rats (NTP, 1982a, b; Takagi et al.,
1990; Lake, 1993).
Many studies have demonstrated that cell proliferation is an important
factor in the development of tumours by both genotoxic and nongenotoxic
agents (Cohen and Ellwein, 1990, 1991). For example, an enhanced rate of
cell replication can increase the frequency of spontaneous lesions and the
probability of converting DNA adducts from both endogenous and
exogenous sources into mutations before they can be repaired (Cohen and
Ellwein, 1990, 1991; Popp and Marsman, 1991). Peroxisome proliferators
are known to produce a burst of cell replication in rodent hepatocytes
during the first few days of administration (Reddy and Lalwani, 1983;
Eacho et al., 1991). In some studies peroxisome proliferators have also
been shown to produce a sustained stimulation of replicative DNA
synthesis (Lake, 1993). Apart from intrinsic compound potency, dose is an
important factor in determining whether a particular compound can
produce either a transient or a sustained stimulation of replicative DNA
synthesis in rodent hepatocytes. For example, low doses of nafenopin and
Wy-14,643 do not produce a sustained stimulation of cell replication,
whereas higher doses do produce this effect (Eacho et al., 1991; Price et al.,
1992; Wada et al., 1992; Lake et al., 1993).
Several studies have demonstrated the presence of numerous foci of
putative preneoplastic cells in the livers of untreated old rats and mice
(Schulte-Hermann et al., 1983; Grasl-Kraupp et al., 1993). These lesions
are considered to represent spontaneously initiated cells as they have
similar biological characteristics to those of cells initiated by genotoxic
carcinogens (Grasl-Kraupp et al., 1993). The ability of peroxisome
proliferators to produce tumours in young compared to old rats has been
investigated in studies with nafenopin (Kraupp-Grasl et al., 1991) and
Wy-14,643 (Cattley et al., 1991). In both studies more adenomas and
carcinomas were produced in old as against young rats.